Protein kinase inhibitors

ABSTRACT

A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (1) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.

TECHNICAL FIELD

The present invention relates to therapeutically active compounds andpharmaceutically acceptable salts thereof which are useful e.g. in thetreatment of cancer.

BACKGROUND OF THE INVENTION

Protein kinases are a class of proteins (enzymes) that regulate avariety of cellular functions. This is accomplished by phosphorylationof specific amino acids on protein substrates resulting inconformational alteration of the substrate protein. The conformationalchange modulates the activity of the substrate or its ability tointeract with other binding partners. Tyrosine kinases are a subset ofprotein kinases that catalyze the transfer of the terminal phosphate ofadenosine triphosphate (ATP) to tyrosine residues on protein substrates.The human genome contains around 90 tyrosine kinases and 43 tyrosinekinase like genes, the products of which regulate cellularproliferation, survival, differentiation, function and motility.

Tyrosine kinases are of two varieties, i.e. receptor and non-receptortyrosine kinases. Receptor tyrosine kinases (e.g., FGFR) aretrans-membrane proteins with a ligand-binding extracellular domain and acatalytic intracellular kinase domain, while non-receptor tyrosinekinases (e.g., c-ABL) lack trans-membrane domains and are found in thecytosol, nucleus and inner surface of cell membrane. Kinase domains ofall tyrosine kinases have bilobar architecture, with an N-terminal lobethat binds ATP and magnesium, a C-terminal lobe containing an activationloop, and a cleft between the lobes to which polypeptide substratesbind.

Receptor tyrosine kinases become activated when ligand binds to theextracellular domain, resulting in receptor oligomerization andautophosphorylation of a regulatory tyrosine within the activation loopof the kinase domain. These phenomena reorient important amino acidresidues, thereby enhancing catalytic activity of the enzyme.

Fibroblast growth factor (FGF) has been recognized as an importantmediator of many physiological processes, such as cell migration,proliferation, survival and differentiation during development andangiogenesis. There are currently over 25 known members of the FGFfamily. The fibroblast growth factor receptor (FGFR) family consists offour members with each composed of an extra cellular ligand bindingdomain, a single trans-membrane domain and an intracellular cytoplasmicprotein tyrosine kinase domain. Upon stimulation with FGF, FGFRs undergodimerisation and transphosphorylation. Upon dimerization, FGFRs activaterange of downstream signaling pathways, such as MAPK and PKB/Aktpathways (Zhou, W. et. al. Chemistry & Biology, 2010, 17, 285). AbnormalFGFR signaling has been reported in many tumor types including multiplemyeloma, gastric, endometrial, prostate and breast (Squires M. et. al.Mol. Cancer Ther., September 2011, 10:1542-1552). FGFs also have role intumor angiogenesis and mediate resistance to vascular endothelial growthfactor receptor 2 (VEGFR2) inhibitors (Casanovas, O. et. al., CancerCell, 2005, 8, 299). Consequently, FGF and FGFRs have the potential toinitiate and/or promote tumorigenesis. Due to this, the FGF signalingsystem happens to be an attractive therapeutic target, mainly becausetherapies targeting FGFRs and/or FGF signaling may affect both the tumorcells and also tumor angiogenesis (Foote, K. M. et. al., WO 2009/019518A1). Consequently, FGF and FGFRs have the potential to initiate and/orpromote tumorigenesis.

SUMMARY OF THE INVENTION

It has been found that compounds of formula (I) inhibit or modulate theactivity of certain protein kinases, more specifically protein tyrosinekinases. In particular, it has been found that the compounds of formula(I) are potent and selective inhibitors of FGFR kinases. The compoundsof the invention have antiproliferative activity and are particularlyuseful in the treatment of cancer.

The compounds of the present invention have a structure represented byformula (I)

wherein

Z is CH or N;

G is cyano, —C(O)NR₁₅R₁₆, —C(O)OR₁₇, —C(O)R₂₁, —C(CH₃)═NOR₂₂ or a groupof formula

wherein A is a phenyl ring or a 5-12 membered heterocyclic ring, and

R₁ is H, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₇ alkyl, C₁₋₇alkoxy, C₁₋₇ alkyl carbonyl, amino, hydroxy, hydroxy C₁₋₇ alkyl, C₁₋₇alkylamino C₁₋₇ alkyl, phenyl C₁₋₇ alkoxy, —NHC(O)—R₂₁, —R₁₂—C(O)—R₁₃,—SO₂—R₁₄ or -E-R₆, and

R₂ is H, halogen, C₁₋₇ alkyl or oxo;

B is a 5-12 membered carbocyclic or heterocyclic ring;

R₃ is H, halogen, C₁₋₇ alkyl, C₁₋₇ alkoxy, cyano or an optionallysubstituted 5-6 membered heterocyclic ring;

R₄ is H, halogen, C₁₋₇ alkyl or oxo;

M is hydroxyl, C₁₋₇ alkyl or —NHR₅;

R₅ is H, —C(O)R₇, —SO₂R₈, —C(O)-D-R₉ or an optionally substituted 5-6membered heterocyclic ring;

R₆ is an optionally substituted 5-6 membered heterocyclic ring;

R₇ is C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₁₋₇ alkoxy, C₁₋₇alkoxy C₁₋₇ alkyl, carboxy C₁₋₇ alkyl, C₁₋₇ alkoxy carbonyl C₁₋₇ alkyl,C₁₋₇ alkylamino C₁₋₇ alkyl, —NH—R₁₀ or —NH—X₁—R₁₁;

R₈ is C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, hydroxy C₁₋₇ alkyl,—NR₁₈R₁₉, —NH—X₂—R₂₀, phenyl or an optionally substituted 5-6 memberedheterocyclic ring;

R₉ is phenyl or an optionally substituted 5-6 membered heterocyclicring;

R₁₀ is C₁₋₇ alkyl or C₃₋₇ cycloalkyl;

R₁₁ is phenyl or an optionally substituted 5-6 membered heterocyclicring;

R₁₂ and R₂₁ are C₁₋₇ alkyl;

R₁₃ is C₁₋₇ alkoxy, amino or hydroxy;

R₁₄ is C₁₋₇ alkyl or C₃₋₇ cycloalkyl;

R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are, independently, H, C₁₋₇ alkyl or C₃₋₇cycloalkyl;

R₂₀ is phenyl or an optionally substituted 5-6 membered heterocyclicring;

R₂₁ is an optionally substituted 5-6 membered heterocyclic ring;

R₂₂ is H or C₁₋₇ alkyl;

E is a bond or a C₁₋₇ alkyl;

D is a bond or a C₁₋₇ alkyl;

X₁ and X₂ are, independently, a bond or C₁₋₇ alkyl;

and pharmaceutically acceptable salts thereof.

In one class of preferred compounds are compounds of formula (I),wherein ring A is any one of the following groups or tautomers thereof:

and R₁ and R₂, as defined above, are attached to the above A-rings.

In another class of preferred compounds are compounds of formula (I),wherein ring B is any one of the following groups or tautomers thereof:

and R₃ and R₄, as defined above, are attached to the above B-rings.

In another class of preferred compounds are compounds of formula (I),wherein Z is CH. In another class of preferred compounds are compoundsof formula (I), wherein Z is N.

A subclass of the above preferred classes are compounds wherein

G is a group of formula

wherein A is a ring of formula (1′), (2′), (3′), (4′), (5′), (7′),(10′), (12′), (14′), (16′) or (20′);

R₁ is H, C₁₋₇ alkyl, C₁₋₇ alkoxy, hydroxy C₁₋₇ alkyl, C₁₋₇ alkylaminoC₁₋₇ alkyl or -E-R₆;

R₂ is H;

B is a ring of formula (1″), (2″), (3″), (4″) or (6″);

E is a bond or C₁₋₇ alkyl;

R₆ is any of the following groups

R₃ is H, halogen, C₁₋₇ alkyl, C₁₋₇ alkoxy;

R₄ is H or halogen;

M is —NHR₅;

R₅ is —C(O)R₇, —SO₂R₈ or —C(O)-D-R₉ or any one of the following groups

R₇ is C₁₋₇ alkyl, C₂₋₇ alkenyl, —NH—R₁₀ or —NH—X₁—R₁₁;

R₈ is C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, hydroxy C₁₋₇ alkyl,—NR₁₈R₁₉, —NH—X₂—R₂₀, phenyl or a group

R₉ is phenyl or a any one of the following groups

R₁₀ is C₁₋₇ alkyl or C₃₋₇ cycloalkyl;

R₁₁ is phenyl, 4-fluorophenyl, or any one of the following groups

R₁₈ and R₁₉ are, independently, H, C₁₋₇ alkyl or C₃₋₇ cycloalkyl;

R₂₀ is a group

X₁ and X₂ are, independently, a bond or C₁₋₇ alkyl, and

D is a bond or C₁₋₇ alkyl.

In one class are compounds of formula (I), wherein M is —NHC(O)R₇,wherein R₇ is C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, —NH—R₁₀ or—NH—X₁—R₁₁, wherein R₁₀ is C₁₋₇ alkyl or C₃₋₇ cycloalkyl, X₁ is a bondor C₁₋₇ alkyl, and R₁₁ is a 5-6 membered heterocyclic ring optionallysubstituted by one or two C₁₋₇ alkyl groups.

In another class are compounds of formula (I), wherein M is —NHSO₂R₈wherein R₈ is C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, phenyl, orNR₁₈R₁₉ wherein R₁₈ and R₁₉ are, independently, H, C₁₋₇ alkyl or C₃₋₇cycloalkyl.

In another class are compounds of formula (I), wherein M is —NHC(O)-D-R₉wherein D is bond or C₁₋₇ alkyl, and R₉ is a 5-6 membered heterocyclicring optionally substituted by one or two C₁₋₇ alkyl groups.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with a pharmaceutically acceptable carrier.

The present invention provides further a use of a compound of formula(I) or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for the treatment of a condition, where FGFR kinaseinhibition is desired.

The present invention provides further a use of a compound of formula(I) or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for the treatment of cancer.

The present invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of acondition, where FGFR kinase inhibition is desired.

The present invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofcancer.

The present invention provides further a method for the treatment of acondition, where FGFR kinase inhibition is desired comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (I).

The present invention provides further a method for the treatment ofcancer comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention can be prepared by a variety of syntheticroutes analogously to the methods known in the literature using suitablestarting materials. The compounds according to formula (I) can beprepared e.g. analogously or according to the following reactionSchemes. Some compounds included in the formula (I) can be obtained byconverting the functional groups of the other compounds of formula (I)obtained in accordance with the following Schemes, by well knownreaction steps such as oxidation, reduction, hydrolysis, acylation,alkylation, amidation, amination, sulfonation and others. It should benoted that any appropriate leaving groups, e.g. N-protecting groups,such as a t-butoxycarbonyl (t-BOC) group or a phenylsulfonyl group, canbe used in well known manner during the syntheses in order to improvethe selectivity of the reaction steps

Compounds of formula (I), wherein G is an optionally substituted A-ringand R₅ is —C(O)CH₃ can be prepared, for example, according to Scheme 1,wherein R₁, R₂, R₃, R₄, ring A, ring B and Z, are as defined above, andR is hydrogen or alkyl. In the method of Scheme 1, theN-(3-bromo-5-nitrophenyl)acetamide [1] is coupled in a suitable solventsuch as 1,2-dimethoxyethane with a boronic acid derivative [2] or asuitable ester thereof in the presence of Pd(dppf)Cl₂ and aqueous sodiumcarbonate at elevated temperature. The nitro group of the obtainedcompound [3] is reduced, e.g. with hydrogen and Pd/C catalyst, ironpowder and aqueous calcium chloride or zinc and aqueous ammoniumchloride, and the resulting amine [4] is reacted with compound [5] in asuitable solvent such as DMF in the presence of potassium fluoride atelevated temperature to obtain compound [6]. In case Z is CH in thecompound [5], X″ is suitably fluoro, and when Z is N, X″ is suitablychloro. The nitro group in compound [6] is reduced, e.g. by using zincand aqueous ammonium chloride or iron powder and aqueous calciumchloride, and the resulting amine [7] is heated with formic acid toproduce compound [8] in a ring closure reaction. Finally, compound [10]is obtained by the Suzuki coupling between compound [8] and a boronicacid derivative [9] or a suitable ester thereof in a suitable solventsuch as 1,2-dimethoxyethane in the presence of Pd(dppf)Cl₂ and aqueoussodium carbonate at elevated temperature.

Alternatively, the compound of formula [3] can be prepared according toScheme 2, wherein R₃, R₄, ring B and R are as defined above, using theboronic acid derivative [11] or a suitable ester thereof in the presenceof Pd(dppf)Cl₂ and aqueous sodium carbonate. Compound [11] can beprepared, e.g. by treating N-(3-bromo-5-nitrophenyl)-acetamide withbis(pinacolato)diboron in the presence of Pd(dppf)Cl₂ and potassiumacetate.

In case the B-ring in the compound [3] is a heterocycle linked to phenylvia a nitrogen heteroatom, the compound [3] can be also prepared using acopper-catalyzed Buchwald amination in the presence of a base suchcesium carbonate or potassium carbonate according to Scheme 3, whereinR₃ and R₄ are as defined above.

In case the B-ring in the compound [3] is pyrrole ring linked to phenylvia a nitrogen atom, the compound [3] can be also prepared from3,5-dinitroaniline [15] and 2,5-dimethoxytetrahydrofuran according toScheme 4. The pyrrole derivative [16] formed is reduced using ammoniumsulphide to obtain compound [17], which is subsequently reacted withacetic anhydride to afford compound [18].

In case where ring A in the compound [10] is an oxazol-5-yl ring, thecompound [10] can be also prepared according to Scheme 5, wherein ringB, R₃ and R₄ are as defined above. In this method the compound [4] istreated with 4-fluoro-3-nitrobenzaldehyde and the resulting compound[20] is thereafter reacted with toluenesulfonylmethyl isocyanide toproduce the oxazol-5-yl compound [21] in a ring closure reaction. Thenitro group of compound [21] can be further reduced, e.g. byhydrogenation, to produce the corresponding amine, which can be thentreated with formic acid according to Scheme 1 to afford the end productin the ring closure reaction.

In case where ring A in the compound [10] is a heterocycle linked to thecarbon atom of the bicyclic ring via a nitrogen heteroatom, the compound[10] can be also prepared using Buchwald coupling according to Scheme 6,wherein X′, ring B, R₁, R₂, R₃, and R₄ are as defined above.

In case where ring A in the compound [10] is an 1H-1,2,3-triazol-4-ylring and R₂ is hydrogen, the compound [10] can be also preparedaccording to Scheme 7, wherein X′, Z, R₁, R₃, R₄ and ring B, are asdefined above. The starting compound [8] is silylated by reacting withethynyltrimethylsilane in the presence oftetrakis(triphenyl-phosphine)palladium(0) (Pd(PPh₃)₄) and Cu(I)iodide toproduce compound [32]. Treatment with TBAF affords the ethynyl compound[33] which can be reacted with azido compound R₁—N₃ in a suitablesolvent, such as DMSO:THF:water (1:1:1) or DMSO:DCM:water (1:1:1) toafford compound [34].

In case where ring A in the compound [10] is a 1-methyl-1H-pyrazol-3-ylring, the compound [10] can be also prepared according to Scheme 8,wherein R₃, R₄ and ring B, are as defined above. In this method thecompound [4] is treated with 1-(4-fluoro-3-nitrophenyl)ethanone and theresulting compound [36] is thereafter reacted with DMF dimethylacetal toproduce the oxazol-5-yl compound [37]. Subsequent treatment with methylhydrazine produces compound [38] in a ring closure reaction. The nitrogroup of compound [38] can be further reduced, e.g. by aqueous ammoniumand zinc, to produce the corresponding amine, which can be then treatedwith formic acid according to Scheme 1 to afford the end product in thering closure reaction.

In case where ring A in the compound [10] is a 1H-imidazol-2-yl ring,the compound [10] can be also prepared according to Scheme 9, whereinR₃, R₄ and ring B, are as defined above. In this method the compound[20] of Scheme 5 is treated with ethylene diamine and N-bromosuccinimideaffording compound [39] in a ring closure reaction. The nitro group ofcompound [39] can be further reduced, e.g. by aqueous ammonium and zinc,to produce the corresponding amine, which can be then treated withformic acid according to Scheme 1 to afford the end product in the ringclosure reaction.

Various compounds of formula (I), wherein R₅ is other than —C(O)CH₃, canbe prepared, for example, according to Scheme 10, wherein R₁, R₂, R₃,R₄, R₇, R₈, R₉, Z, D, ring A and ring B are as defined above. Theacetamide compound [10] can be converted to its corresponding amine[24], for example, by heating in ethanol in the presence of a base, suchas aqueous sodium hydroxide or potassium hydroxide, or an acid such asaqueous HCl. The obtained amine [24] can be used as a starting materialfor subsequent reaction steps. The compounds of formula (I), wherein R₅is —SO₂R₈ can be prepared, for example, by treating the amine [24] withCl—SO₂R₈ in suitable solvent such as DCM in the presence of pyridine.Compounds of formula (I), wherein R₅ is —C(O)R₇ and R₇ is C₁₋₇alkyl orC₁₋₇ alkylamino C₁₋₇ alkyl, can be prepared, for example, by reactingthe amine [24] with HOOC—R₇ in suitable solvent such as DMF in thepresence of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) and DIPEA. Compounds of formula(I), wherein R₅ is —C(O)-D-R₉ can be prepared, for example, by reactingthe amine [24] with HOOC-D-R₉ in suitable solvent such as DMF in thepresence of EDC, HOBt and DIPEA. Compounds of formula (I), wherein R₅ is—C(O)-D-R₉, D is a bond and R₉ is a heterocyclic ring linked to thecarbonyl carbon atom via nitrogen heteroatom, can be prepared byreacting the amine [24] with phosgene and then with compound [29] asshown in Scheme 10.

Compounds of formula (I), wherein R₇ is —NH—R₁₀ or —NH—X—R₁₁, can beprepared, for example, according to Scheme 11 by reacting the amine [24]in a suitable solvent such n-butanol with isocyanato derivativesO═C═N—R₀ or O═C═N—X—R₁₁ in the presence of suitable base such astriethylamine (TEA). Alternatively, compounds wherein R₇ is —NH—X—R₁₁can be prepared by treating amine [24] in suitable solvent such as DCMwith phosgene and then with H₂N—X—R₁₁, see Scheme 11.

Compounds wherein G is other than optionally substituted ring A, can beprepared analogously using the methods of Scheme 1, wherein X′ isreplaced by G. Compounds of formula (I) wherein G is —C(O)NH₂ can bealso prepared by heating compound [8], wherein X′ is cyano, in aqueouspotassium hydroxide.

Compounds wherein M is a hydroxy group can be suitably prepared from acompound of formula [42] followed by the bicyclic ring closure as inScheme 1 and addition of the B-ring by e.g. Suzuki coupling as inScheme 1. The alkoxy group of the obtained compound can be transformedinto the hydroxy group e.g. by heating the alkoxy compound in thepresence of thiourea/AlCl₃ reagent pair.

Finally, compounds wherein R₅ is an optionally substituted 5-6 memberedheterocyclic ring can be prepared according to Scheme 12 or 13 startingfrom a compound [40] or [42], wherein R₃, R₄, Z, ring B and G are asdefined above, using palladium (e.g. Pd₂(dba)₃) catalyzed C—N couplingin the presence of a metal chelating ligand such as Xantphos.

Pharmaceutically acceptable salts, e.g. acid addition salts with bothorganic and inorganic acids are well known in the field ofpharmaceuticals. Non-limiting examples of these salts include chlorides,bromides, sulfates, nitrates, phosphates, sulfonates, formates,tartrates, maleates, citrates, benzoates, salicylates and ascorbates.Pharmaceutically acceptable esters, when applicable, may be prepared byknown methods using pharmaceutically acceptable acids that areconventional in the field of pharmaceuticals and that retain thepharmacological properties of the free form. Non-limiting examples ofthese esters include esters of aliphatic or aromatic alcohols, e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butylesters. Phosphate esters and carbonate esters, are also within the scopeof the invention.

The terms employed herein have the following meanings:

The term “halo” or “halogen”, as employed herein as such or as part ofanother group, refers to chlorine, bromine, fluorine or iodine. Fluorineis a preferred halogen.

The term “C₁₋₇ alkyl”, as employed herein as such or as part of anothergroup, refers to a straight or branched chain saturated hydrocarbongroup having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s). Representativeexamples of C₁₋₇ alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl and n-hexyl. One preferred embodiment of “C₁₋₇alkyl” is C₁₋₃ alkyl. The term “C₁₋₃ alkyl” refers to an preferredembodiment of “C₁₋₇ alkyl” having 1, 2 or 3 carbon atoms.

The term “C₃₋₇ cycloalkyl”, as employed herein as such or as part ofanother group, refers to a saturated cyclic hydrocarbon group containing3, 4, 5, 6 or 7 carbon atoms. Representative examples of cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

The term “C₃₋₇ cycloalkyl C₁₋₇ alkyl”, as employed herein refers to aC₃₋₇ cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a C₁₋₇ alkyl group, as defined herein.

The term “C₂₋₇ alkenyl”, as employed herein as such or as part ofanother group, refers to an aliphatic hydrocarbon group having 2 to 7carbon atoms and containing one or several double bonds. Representativeexamples include, but are not limited to, ethenyl, propenyl andcyclohexenyl.

The term “hydroxy”, as employed herein as such or as part of anothergroup, refers to an —OH group. The term “cyano”, as employed herein assuch or as part of another group, refers to a —CN group. The term“amino”, as employed herein as such or as part of another group, refersto a —NH₂ group. The term “carboxy”, as employed herein as such or aspart of another group, refers to —COOH group. The term “carbonyl”, asemployed herein as such or as part of another group, refers to a carbonatom double-bonded to an oxygen atom (C═O). The term “oxo”, as employedherein as such or as part of another group, refers to oxygen atom linkedto another atom by a double bond (═O).

The term “C₁₋₇ alkoxy”, as employed herein as such or as part of anothergroup, refers to C₁₋₇ alkyl, as defined herein, appended to the parentmolecular moiety through an oxygen atom. Representative examples of C₁₋₇alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy,isobutoxy, sec-butoxy and tert-butoxy.

The term “hydroxyl C₁₋₇ alkyl”, as employed herein, refers to at leastone hydroxy group, as defined herein, appended to the parent molecularmoiety through a C₁₋₇ alkyl group, as defined herein. Representativeexamples of hydroxyl C₁₋₇ alkyl include, but are not limited to,hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,1-hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-1-hydroxypropyl.

The term “halo C₁₋₇ alkyl”, as employed herein, refers to at least onehalogen, as defined herein, appended to the parent molecular moietythrough a C₁₋₇ alkyl group, as defined herein. Representative examplesof halo C₁₋₇ alkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl.

The term “cyano C₁₋₇ alkyl”, as employed herein, refers to a cyanogroup, as defined herein, appended to the parent molecular moietythrough a C₁₋₇ alkyl group, as defined herein. Representative examplesof cyano C₁₋₇ alkyl include, but are not limited to, cyanomethyl,1-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl.

The term “carboxy C₁₋₇ alkyl”, as employed herein as such or as part ofanother group, refers to a carboxy group, as defined herein, appended tothe parent molecular moiety through a C₁₋₇ alkyl group, as definedherein.

The term “halogen C₁₋₇ alkoxy”, as employed herein, refers to at leastone halogen, as defined herein, appended to the parent molecular moietythrough a C₁₋₇ alkoxy group, as defined herein.

The term “phenyl C₁₋₇ alkoxy”, as employed herein, refers to at leastone phenyl group appended to the parent molecular moiety through a C₁₋₇alkoxy group, as defined herein.

The term “C₁₋₇ alkylcarbonyl”, as employed herein as such or as part ofanother group, refers to a C₁₋₇ alkyl group, as defined herein, appendedto the parent molecular moiety through a carbonyl group, as definedherein.

The term “C₁₋₇ alkoxycarbonyl”, as employed herein as such or as part ofanother group, refers to a C₁₋₇ alkoxy group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein.

The term “C₁₋₇ alkoxycarbonyl C₁₋₇ alkyl”, as employed herein as such oras part of another group, refers to a C₁₋₇ alkoxycarbonyl group, asdefined herein, appended to the parent molecular moiety through a C₁₋₇alkyl group, as defined herein.

The term “aminocarbonyl”, as employed herein as such or as part ofanother group, refers to an amino group, as defined herein, appended tothe parent molecular moiety through a carbonyl group, as defined herein.

The term “amino C₁₋₇ alkyl”, as employed herein, refers to at least oneamino group, as defined herein, appended to the parent molecular moietythrough a C₁₋₇ alkyl group, as defined herein. Representative examplesof amino C₁₋₇ alkyl include, but are not limited to, aminomethyl,2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl,2-aminopropyl, 4-aminobutyl and 1-methyl-1-aminoethyl.

The term “C₁₋₇ alkylamino”, as employed herein as such or as part ofanother group, refers to at least one C₁₋₇ alkyl group, as definedherein, appended to the parent molecular moiety through an amino group,as defined herein. Representative examples of C₁₋₇ alkylamino include,but are not limited to methylamino, ethylamino, propylamino, butylamino,dimethylamino, diethylamino and N-ethyl-N-methylamino.

The term “C₁₋₇ alkylamino C₁₋₇ alkyl”, as employed herein as such or aspart of another group, refers to at least one C₁₋₇ alkylamino group, asdefined herein, appended to the parent molecular moiety through an C₁₋₇alkyl group, as defined herein.

The term “carboxy C₁₋₇ alkylamino”, as employed herein as such or aspart of another group, refers to at least one carboxy group, as definedherein, appended to the parent molecular moiety through an C₁₋₇alkylamino group, as defined herein

The term “C₁₋₇ alkoxy C₁₋₇ alkyl”, as employed herein, refers to atleast one C₁₋₇ alkoxy group, as defined herein, appended to the parentmolecular moiety through an C₁₋₇ alkyl group, as defined herein.

The term “C₁₋₇ alkoxycarbonyl C₁₋₇ alkyl”, as employed herein, refers toat least one C₁₋₇ alkoxycarbonyl group, as defined herein, appended tothe parent molecular moiety through an C₁₋₇ alkyl group, as definedherein.

The term “substituted” as used herein in connection with variousresidues refers to halogen substituents, such as fluorine, chlorine,bromine, iodine, or C₁₋₇ alkyl, C₃₋₇ cycloalkyl, halo C₁₋₇ alkyl,hydroxy, amino, C₁₋₇ alkoxy, C₁₋₇ acyl C₁₋₇ alkylamino, amino C₁₋₇alkyl, nitro, cyano, thiol or methylsulfonyl substituents. Preferred arehalogen, C₁₋₇ alkyl, halo C₁₋₇ alkyl, hydroxy, amino, C₁₋₇ alkoxy andmethylsulfonyl substituents. In one group of preferred substituents areone or two C₁₋₇ alkyl substituents, particularly one or two C₁₋₃ alkylsubstituents, particularly selected from methyl and ethyl substituents.

The “substituted” groups may contain 1 to 3, preferably 1 or 2, of theabove mentioned substituents.

The term “5-6 membered heterocyclic ring” as employed herein, refers toa saturated, partially saturated or aromatic ring with 5 or 6 ringatoms, of which 1-4 atoms are heteroatoms selected from a groupconsisting of N, O and S. Representative examples of 5-6-memberedheterocyclic ring include, but are not limited to, pyrazolyl,1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, pyrimidinyl, pyridinyl,tetrazolyl, piperazinyl, furanyl, morpholinyl, piperidinyl,pyrrolidinyl, thiazolyl, isoxazolyl, pyrazinyl tetrahydropyranyl,1,2,4-oxadiazolyl, oxazolyl, imidazolyl, indolyl and4,5-dihydroimidazolyl rings.

The term “5-12 membered heterocyclic ring” as employed herein, refers toa monocyclic or bicyclic saturated, partially saturated or aromatic ringwith 5 to 12 ring atoms, of which 1-5 atoms are heteroatoms selectedfrom a group consisting of N, O and S. Representative examples of 5-12membered heterocyclic ring include the examples given above andadditionally, but not limited to, indazolyl, pyrazolo[1,5-a]pyrimidinyl,benzo[d]imidazolyl, imidazo[4,5-b]pyridinyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl and benzofuranyl rings.

The term “5-12 membered carbocyclic ring” as employed herein, refers toa saturated, partially saturated or aromatic ring with 5 to 12 ringatoms consisting of carbon atoms only. Representative examples of 5-12membered carbocyclic ring include, but are not limited to, phenyl,naphtyl and cyclohexyl rings.

The definition of formula (I) above is inclusive of all the possiblestereoisomers of the compounds, including geometric isomers, e.g. Z andE isomers (cis and trans isomers), and optical isomers, e.g.diastereomers and enantiomers, and all prodrug esters, e.g. phosphateesters and carbonate esters, and isotopes. Furthermore, the inventionincludes in its scope both the individual isomers and any mixturesthereof, e.g. racemic mixtures. The individual isomers may be obtainedusing the corresponding isomeric forms of the starting material or theymay be separated after the preparation of the end compound according toconventional separation methods. For the separation of optical isomers,e.g. enantiomers, from the mixture thereof the conventional resolutionmethods, e.g. fractional crystallisation, may be used.

Compounds of the invention may be administered to a patient intherapeutically effective amounts which range usually from about 0.1 toabout 2000 mg per day depending on the age, weight, ethnic group,condition of the patient, condition to be treated, administration routeand the active ingredient used. The compounds of the invention can beformulated into dosage forms using the principles known in the art. Thecompound can be given to a patient as such or in combination withsuitable pharmaceutical excipients in the form of tablets, granules,capsules, suppositories, emulsions, suspensions or solutions. Choosingsuitable ingredients for the composition is a routine for those ofordinary skill in the art. Suitable carriers, solvents, gel formingingredients, dispersion forming ingredients, antioxidants, colours,sweeteners, wetting compounds and other ingredients normally used inthis field of technology may be also used. The compositions containingthe active compound can be given enterally or parenterally, the oralroute being the preferred way. The contents of the active compound inthe composition is from about 0.5 to 100%, preferably from about 0.5 toabout 20%, per weight of the total composition.

The compounds of the invention can be given to the subject as the soleactive ingredient or in combination with one of more other activeingredients for treatment of a particular disease, for example cancer.

The present invention will be explained in more detail by the followingexperiments and examples. The experiments and examples are meant onlyfor illustrating purposes and do not limit the scope of the inventiondefined in claims.

EXPERIMENTS

1. Inhibition of FGFR1 and other kinases

Methods FGFR1 Assay

Compounds were screened in the TR-FRET assay with FGFR1 kinase. 5 ng ofFGFR1 [Upstate, USA] kinase was used for assay. The compound wasincubated with the kinase for 30 minutes at RT. After the incubation,substrate mix [40 nM Ultra light poly GT (Perkin Elmer, USA) and 13 μMATP (Sigma)] was added. The above reaction was stopped by the additionof 40 mM EDTA after the 30 min kinase reaction. The Eu-labelledantiphospho-tyrosine antibody [Perkin Elmer, USA] was added at 0.5 nMand the fluorescence emission at 615 nm/665 nm [excitation at 340 nm]was measured. The compounds were initially screened at 100 nM and 1 μMconcentrations. The compounds with >50% inhibition at 100 nM of FGFR1were taken for the full dose response studies. The final DMSOconcentration in the assay was 1%. For IC₅₀ determination, ⅓^(rd) serialdilution was made from the 20 mM DMSO stock solution. 2 μl of these weretransferred to the test wells containing 20 μl of the reaction mixture[total reaction volume 20 μl]. The fluorescence was measured in PerkinElmer Wallac 1420 Multilabel Counter Victor 3. The IC₅₀ was determinedby fitting the dose response data to sigmoidal curve fitting equationusing GraphPad Prism software V5.

c-Met Assay

Compounds were screened in the TR-FRET assay with c-Met kinase. 0.1 ngof c-Met [expressed in-house] kinase was used for assay. The compoundwas incubated with the kinase for 60 min at RT. After the incubation,substrate mix [40 nM Ultra light poly GT (Perkin Elmer, USA) and 10 μMATP (Sigma)] was added. The above reaction was stopped by the additionof 40 mM EDTA after the 30 min kinase reaction. The Eu-labelledantiphospho-tyrosine antibody [Perkin Elmer, USA] was added at 0.5 nMand the fluorescence emission at 615 nm/665 nm [excitation at 340 nm]was measured. The compounds were initially screened at 100 nM and 1 μMconcentrations. The compounds with >50% inhibition at 100 nM of c-Metwere taken for the full dose response studies. The final DMSOconcentration in the assay was 1%. For IC₅₀ determination, ⅓^(rd) serialdilution was made from the 20 mM DMSO stock solution. 2 μl of these weretransferred to the test wells containing 20 μl reaction mixture [totalreaction volume 20 μl]. The fluorescence was measured in Perkin ElmerWallac 1420 Multilabel Counter Victor 3. The IC50 was determined byfitting the dose response data to sigmoidal curve fitting equation usingGraphPad Prism software V5.

Results

Enzymatic activity and selectivity of selected compounds of theinvention on different kinases is presented in Table 1. The compounds ofthe invention were found to be potent and selective FGFR kinaseinhibitors.

TABLE 1 Inhibition of FGFR1 and c-Met kinase Inhibition (%) of IC₅₀ ofFGFR1 Inhibition (%) of Compound FGFR1 at 1000 nM inhibition (nM) c-Metat 1000 nM Example 5 95 12 7 Example 22 99 3.8 5 Example 25 93 34 12Example 26 93 21 2 Example 30 94 16 1 Example 38 88 33 0 Example 47 99 710 Example 49 98 3.4 9 Example 69 87 22 −2 Example 70 99 10 0 Example 7298 32 11 Example 82 96 16 15 Example 83 95 37 5 Example 112 97 1.8 0Example 119 94 83 23 Example 123 94 61 0 Example 127 91 62 10 Example131 99 1.3 15 Example 133 97 14 0 Example 134 92 98 0 Example 142 91 480 Example 152 79 7.3 0 Example 155 89 62 1 Example 158 95 22 12 Example169 89 94 nd Example 170 92 59 nd Example 178 86 14.9 nd Example 190 964.3 nd Example 204 98 20 nd Example 217 91 10.4 nd Example 241 97 2.9 ndExample 244 98 14 nd Example 280 80 90 nd Example 281 96 9 nd Example220 97 3.4 nd Example 289 94 32 nd Example 294 99 9.3 nd Example 319 9718 nd Example 322 92 65.8 nd Example 259 92 45 nd nd = not determined

The preparation of the compounds of the invention is illustrated by thefollowing Examples.

EXAMPLES

LCMS data has been recorded in +ve mode unless otherwise mentioned.

Intermediate Example 1N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanaminea) 2-(4-Bromo-1H-pyrazol-1-yl)-N,N-dimethylethanamine

To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF were addedK₂CO₃ (11.75 g, 85.03 mmol, 2.5 eq.) and 2-chloro-N,N-dimethylethanamineHCl (7.35 g, 51 mmol, 1.5 eq) and the mixture was stirred at RT for 12h. The mixture was quenched with water and extracted with DCM (3×150ml). The combined organic layer was washed with water, brine and driedover sodium sulphate. The solvent was distilled off to afford the cruderesidue which was purified by column chromatography (60-120 silica gel,1% methanol in DCM) to give the product in 86% yield (6.4 g). ¹H NMR(300 MHz, DMSO-d₆): δ 7.95 (s, 1H), 7.25 (s, 1H), 4.18 (t, 2H), 2.61 (t,2H), 2.15 (s, 6H); LC-MS (ESI): Calculated mass: 218.09; Observed mass:219.8[M+H]⁺ (RT: 0.439 min).

b)N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine

To a degassed (N₂ bubbling) solution of the compound of IntermediateExample 1(a) (10 g, 45.85 mmol) in 1,4-dioxane (50 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (17.47 g,68.78 mmol, 1.5 eq.), Pd(dppf)Cl₂ (1.87 g, 2.29 mmol, 0.05 eq.) andpotassium acetate (11.23 g, 114.6 mmol, 2.5 eq.). The mixture was heatedat 100° C. in a sealed tube for 12 h. The mixture was diluted with ethylacetate and filtered over a pad of celite. The solvent was distilled offto give the product (7.0 g). LC-MS (ESI): Calculated mass: 265.16;Observed mass: 266.2 [M+H]⁺ (RT: 0.09 min).

Intermediate Example 24-(2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)-morpholine

The compound was synthesized using the procedure described in Example 1.LC-MS (ESI): Calculated mass: 307.2; Observed mass: 308.1 [M+H]⁺ (RT:0.11 min).

Intermediate Example 3 1-Fluoro-4-iodo-2-nitrobenzene

To a solution of 1-fluoro-2-nitrobenzene (5 g, 35.43 mmol) in triflicacid (15.6 ml, 177.15 mmol, 5 eq.) at 0° C. was added N-iodosuccinimide(9.57 g, 42.5 mmol, 1.2 eq.) portionwise and the mixture was stirred atRT for 1 h. The mixture was quenched by the addition of water andextracted with diethylether (3×150 ml). The combined organic layer waswashed with water, aqueous sodium thiosulfate, brine and dried oversodium sulphate. The solvent was distilled off and the crude residue waspurified by column chromatography (60-120 silica gel, 5% ethyl acetatein hexane) to afford the compound in 66% yield (6.2 g). ¹H NMR (300 MHz,DMSO-d₆): δ 8.42 (dd, 1H), 8.18-8.13 (m, 1H), 7.46-7.39 (m, 1H).

Intermediate Example 4 4-Fluoro-3-nitrobenzaldehyde

Nitration mixture (sulfuric acid 40 ml+nitric acid 5.5 ml) was addeddropwise to 4-fluorobenzaldehyde (10 g, 80.57 mmol) at 0° C. and themixture was stirred at 5° C. for 20 min and at RT for 1 h. The mixturewas quenched by the addition of crushed ice. The precipitate formed wasfiltered and was washed repeatedly with water to give white solid. Thesolid was dried under vacuum to give the product in 77% yield (10.5 g).¹H NMR (300 MHz, CDCl₃): δ 10.04 (s, 1H), 8.58 (dd, 1H), 8.22-8.18 (m,1H), 7.5 (t, 1H).

Intermediate Example 5 tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-piperidine-1-carboxylatea) tert-Butyl 4-hydroxypiperidine-1-carboxylate

To a solution of piperidin-4-ol (3.5 g, 34.6 mmol) in CH₂Cl₂ (50 ml) at0° C. were added Boc₂O (11.3 g, 51.9 mmol, 1.5 eq) and Et₃N (7.2 ml,51.9 mmol, 1.5 eq). The mixture was stirred at RT for 1 h and quenchedand extracted as in Intermediate Example 1(a). The solvent was distilledoff to give the crude product (7.0 g).

b) tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate

The compound of the Intermediate Example 5(a) (7 g, 34.7 mmol) wasdissolved in CH₂Cl₂ (70 ml) at 0° C. Et₃N (10 ml, 69.4 mmol, 2 eq.) andmethanesulfonyl chloride (2.7 ml, 34.7 mmol, 1 eq.) were added. Themixture was stirred at RT for 3 h and quenched and extracted as inprevious example. The solvent was distilled off to afford the crudeproduct (6.7 g).

c) tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a cooled solution of the compound of Intermediate Example 5(b) (6.7g, 23.9 mmol) in DMF (50 ml) was added NaH (2.8 g, 119 mmol, 5 eq.) and4-bromo-1H-pyrazole (2.8 g, 19.1 mmol, 0.8 eq.) and stirred at 80° C.for 12 h. The mixture was quenched and extracted with ethyl acetate(3×100 ml). The combined organic layer was washed with water, brine anddried over sodium sulphate. The solvent was distilled off to afford thecrude product (8.0 g).

d) tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a (N₂ bubbling) solution of the compound of Intermediate Example 5(c)(8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-(1,3,2-dioxaborolane) (7.36 g, 29mmol, 1.2 eq.), Pd(dppf)Cl₂ (2 g, 2.42 mmol, 0.1 eq.) and potassiumacetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of IntermediateExample 1(b). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 10% ethyl acetate inhexane) to give the product in 59% yield (5.4 g). LC-MS (ESI):Calculated mass: 377.29; Observed mass: 378.3 [(M+H]⁺ (RT: 1.83 min).

Intermediate Example 6 4-Azido-2-methylbutan-2-ol a)4-Bromo-2-methylbutan-2-ol

To a cooled solution of ethyl 3-bromopropanoate (0.5 g, 2.8 mmol) indiethyl ether (50 ml) at 0° C. was added methyl magnesium bromide (0.98g, 8.3 mmol, 3 eq.) dropwise over 5 min and the mixture was allowed tostir until TLC showed complete absence of the starting material. Themixture was quenched and extracted as in Intermediate Example 5(c). Thesolvent was distilled off to give the crude product (0.4 g).

b) 4-Azido-2-methylbutan-2-ol

To a mixture of 4-bromo-2-methylbutan-2-ol (0.4 g, 2.4 mmol) andtriethylamine (1 ml, 7 mmol, 3 eq.) in CH₂Cl₂ (15 ml) was added sodiumazide (0.47 g, 7 mmol, 3 eq.) in H₂O (5 ml) and the mixture was allowedto stir overnight. The mixture was quenched with water and extractedwith CH₂Cl₂ (3×50 ml). The combined organic layer was washed with water,brine and dried over sodium sulphate. The solvent was distilled off toafford the product in 65% yield (0.2 g). ¹H NMR (300 MHz, DMSO-d₆): δ4.39 (br s, 1H), 3.40-3.32 (m, 2H), 1.15 (t, 2H), 1.23-1.04 (m, 6H).

Intermediate Example 7 Azidocyclopentane

To a solution of iodocyclopentane (0.5 g, 2.55 mmol) in DMF (2 ml) wasadded aqueous sodium azide (0.33 g, 5.1 mmol). The mixture stirred at RTfor 10 min, and then stirred at 80° C. overnight. The mixture wasextracted with diethyl ether (3×50 ml) and the combined organic layerwas washed with water, brine and dried over sodium sulphate. The solventwas distilled off to afford the product in 64% yield (0.18 g) which wasdirectly used for the next step. FTIR (neat): v 3448, 2471, 2100, 1671,1498, 1438, 1383, 1256, 1094, 865 cm⁻¹.

Intermediate Example 8 (Azidomethyl)cyclobutane

To a solution of (bromomethyl)cyclobutane (0.5 g, 3.35 mmol) in DMF (2ml) was added aqueous sodium azide (0.43 g, 6.7 mmol). The mixture wasstirred at RT for 10 min, followed by stirring at 80° C. overnight. Themixture was extracted as in the previous example. The solvent wasdistilled off to give the product in 54% yield (0.2 g). ¹H NMR (300 MHz,DMSO-d₆): δ 3.66-3.53 (m, 2H), 2.66-2.21 (m, 1H), 2.06-2.00 (m, 2H),1.84-1.66 (m, 4H).

Intermediate Example 91-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolea) 4-Bromo-1-(cyclopropylmethyl)-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (0.1 g, 0.68 mmol) in DMF (20 ml)were added K₂CO₃ (0.19 g, 1.36 mmol, 2 eq.) and(bromomethyl)cyclopropane (92 mg, 0.68 mmol, 1 eq.). The mixture wasstirred at RT for 4 h. The mixture was quenched and extracted as inIntermediate Example 5(c). The solvent was distilled off to afford thecrude product (0.15 g).

b)1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a degassed (N₂ bubbling) solution of the compound of IntermediateExample 9(a) (0.15 g, 0.75 mmol) in 1,4-dioxane (10 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.23 g, 0.9mmol, 1.2 eq.), Pd(dppf)Cl₂ (0.12 g, 0.15 mmol, 0.2 eq.) and potassiumacetate (0.25 g, 2.55 mmol, 3.4 eq.). using the procedure ofIntermediate Example 1(b). The solvent was distilled off to afford thecrude residue which was purified by column chromatography (60-120 silicagel, 30% ethyl acetate in hexane) to give the product in 81% yield (0.15g). LC-MS (ESI): Calculated mass: 248.13; Observed mass: 249.2 [(M+H]⁺(rt: 1.58 min).

Intermediate Example 10 2-Morpholinoacetic acid a) Ethyl2-morpholinoacetate

To a solution of ethyl 2-chloroacetate (0.5 g, 5.74 mmol) in DMF (70 ml)at 10° C. were added K₂CO₃ (1.98 g, 14.34 mmol, 2.5 eq.) and1-methylpiperazine (1.05 g, 8.6 mmol, 1.5 eq.) and the mixture wasstirred at RT for 2 h. The mixture was quenched and extracted as inIntermediate Example 5(c). The solvent was distilled off and the cruderesidue was purified by column chromatography (60-120 silica gel, 40%ethyl acetate in hexane) to afford the product in 74% yield (0.74 g).LC-MS (ESI): Calculated mass: 173.2, Observed mass: 174.0 [M+H]⁺ (rt:0.20 min).

b) 2-Morpholinoacetic acid

A solution of ethyl 2-morpholinoacetate (1.8 g, 11.44 mmol) in 8 N HCl(5 ml) was heated at 90° C. for 12 h. The mixture was concentrated togive the product in 64% yield (0.9 g). LC-MS (ESI): Calculated mass:145.16; Observed mass: 146.3 [M+H]⁺ (rt: 0.21 min).

Intermediate Example 11 4-Azido-1-methylpiperidine a)1-Methylpiperidin-4-yl methanesulfonate

1-Methylpiperidin-4-ol (4 g, 34.7 mmol) was dissolved in CH₂Cl₂ (70 ml)at 0° C. followed by the addition of Et₃N (10 ml, 69.4 mmol, 2 eq.) andmethanesulfonyl chloride (2.7 ml, 34.7 mmol, 1 eq.). The mixture wasstirred at RT for 3 h and quenched and extracted as in IntermediateExample 5(a). The solvent was distilled off to afford the crude product(6.7 g).

b) 4-Azido-1-methylpiperidine

To a solution of the compound of Intermediate Example 11(a) (2.1 g, 10.9mmol) in DMF (30 ml) was added sodium azide (1 g, 16.32 mmol, 1.5 eq.)The mixture was stirred at 60° C. for 12 h. The mixture was thenquenched with water and extracted with diethylether (3×100 ml). Thecombined organic layer was washed with water, brine and dried oversodium sulphate. The solvent was distilled off to give the product (1.3g). ¹H NMR (300 MHz, CDCl₃): δ 3.49-3.37 (m, 1H), 2.71-2.67 (m, 2H) 2.24(s, 3H) 2.18-2.09 (m, 2H) 1.93-1.85 (m, 2H) 1.72-1.60 (m, 2H); LC-MS(ESI); Calculated mass: 140.1: Observed mass: 141.1 [M+H]⁺ (rt: 0.13min).

Intermediate Example 121-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolea) 4-Bromo-1-isopropyl-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF (70 ml) wereadded K₂CO₃ (11.83 g, 85.6 mmol, 2.5 eq.) and 2-bromopropane (6.3 g,51.36 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h. Themixture was quenched and extracted as in Intermediate Example 5(a). Thesolvent was distilled off and the crude residue was purified by columnchromatography (60-120 silica gel, 20% ethyl acetate in hexane) toafford the product in 89% yield (5.8 g). ¹H NMR (300 MHz, DMSO-d₆): δ8.01 (s, 1H), 7.50 (s, 1H), 4.49-4.43 (m, 1H), 1.38 (d, 6H).

b)1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a degassed (N₂ bubbling) solution of the compound of IntermediateExample 12(a) 4-bromo-1-isopropyl-1H-pyrazole (1.5 g, 7.9 mmol) in1,4-dioxane (30 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3 g, 11.84mmol, 1.5 eq.), Pd(dppf)Cl₂ (0.64 g, 0.79 mmol, 0.1 eq.) and potassiumacetate (1.93 g, 19.74 mmol, 2.5 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off to afford theproduct in 67% yield (1.2 g). LC-MS (ESI): Calculated mass: 236.12;Observed mass: 237.1 [M+H]⁺ (rt: 1.41 min).

Intermediate Example 131-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole a)4-Bromo-1-ethyl-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF were addedK₂CO₃ (11.75 g, 85.03 mmol, 2.5 eq.) and iodoethane (8 g, 51 mmol, 1.5eq.) and the mixture was stirred at RT for 12 h. The mixture wasquenched and extracted as in Intermediate Example 5(c). The solvent wasdistilled off and the crude residue was purified by columnchromatography (60-120 silica gel, 40% ethyl acetate in hexane) to yieldthe product in 84% yield (5 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.02 (s,1H), 7.55 (s, 1H), 4.15 (q, 2H), 1.37 (t, 3H); LC-MS (ESI): Calculatedmass: 175.03; Observed mass: 177.0 [M+H]⁺ (rt: 0.56 min).

b) 1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a degassed (N₂ bubbling) solution of 4-bromo-1-ethyl-1H-pyrazole (2g, 11.42 mmol) in 1,4-dioxane (30 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-(1,3,2-dioxaborolane) (4.35 g,17.14 mmol, 1.5 eq.), Pd(dppf)Cl₂ (0.93 g, 1.14 mmol, 0.1 eq.) andpotassium acetate (2.79 g, 28.55 mmol, 2.5 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off to give theproduct in 88% yield (2.2 g). LC-MS (ESI): Calculated mass: 222.09;Observed mass: 223.3 [M+H]⁺ (rt: 0.83 min).

Intermediate Example 14 2-Chloro-5-iodo-3-nitropyridine a)5-Iodo-3-nitropyridin-2-amine

To a solution of 3-nitropyridin-2-amine (1.2 g, 8.63 mmol) in aceticacid (5 ml), water (1 ml) and sulfuric acid (0.2 ml) was added periodicacid (0.4 g, 1.72 mmol, 0.2 eq.) and the mixture was stirred at 90° C.for 15 min. Iodine (0.87 g, 3.45 mmol, 0.4 eq.) was added portionwiseand the mixture was heated at 90° C. for 1 h. The mixture was quenchedby the addition of water and extracted with ethylacetate (3×150 ml). Thecombined organic layer was washed with water, aqueous sodiumthiosulfate, brine and dried over sodium sulphate. The solvent wasdistilled off to give the product in 57% yield (1.3 g). ¹H NMR (300 MHz,DMSO-d₆): δ 8.58 (d, 1H), 8.54 (d, 1H) 8.04 (br s, 2H); LC-MS (ESI);Calculated mass: 265.01: Observed mass: 265.9 [M+H]⁺ (rt: 1.36 min).

b) 2-Chloro-5-iodo-3-nitropyridine

To a solution of 5-iodo-3-nitropyridin-2-amine (1.3 g, 4.9 mmol) inconcentrated HCl at 0° C. was added sodium nitrite (6.73 g, 97.13 mmol,20 eq.) stepwise followed by the addition of copper(I) chloride (0.5 g,4.9 mmol, 1 eq.) and the mixture was stirred at RT for 12 h. The mixturewas then poured in to a mixture of ammonium hydroxide and water (1:1)and extracted with ethylacetate (3×150 ml). The combined organic layerwas washed with water, aqueous sodium thiosulfate, brine and dried oversodium sulphate. The solvent was distilled off to afford the product in43% yield (0.6 g).

Intermediate Example 15 2-(4-Ethylpiperazin-1-yl) acetic acid a) Ethyl2-(4-methylpiperazin-1-yl)acetate

To a solution of 1-methylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMFwere added K₂CO₃ (265 m g, 21.927 mmol, 2.5 eq) and ethyl 2-bromoacetate(167 mg, 13.15 mmol, 1.5 eq). The mixture was stirred at RT for 16 h andquenched and extracted as in Intermediate Example 5(a). The solvent wasdistilled off to afford the product in 76.4% yield. (1.3 g).

b) 2-(4-Ethylpiperazin-1-yl) acetic acid

The solution of methyl 2-(4-ethylpiperazin-1-yl)acetate (1.3 g, 6.50mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h and concentratedon vacuum pump. The mixture was quenched with sodium bicarbonatesolution and extracted with ethyl acetate (3×150 ml). The combinedorganic layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to give the product in 54.5%yield (0.6 g). LC-MS (ESI): Calculated mass: 158.0; Observed mass: 159.1[M+H]⁺ (rt: 0.102 min).

Intermediate Example 16 N-cyclopropyl-2-oxooxazolidine-3-sulfonamide

To a solution of bromoethanol (1 g, 8.06 mmol) in DCM was added chlorosulfonyl isocyanate (1.13 g, 8.06 mmol) in DCM and this solution addedover 2 min, dropwise, to cyclopropyl amine (0.552 g, 0.009 mmol) andtriethylamine (1 ml, 0.007 mmol) in DCM and stirred at RT for 1 h. Themixture was quenched with 0.2 M HCl solution and extracted with DCM(3×150 ml). The combined organic layer was washed with water, brine anddried over sodium sulphate. The solvent was distilled off to afford theproduct in 48% yield (0.8 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.15-8.14 (d,1H), 4.42 (t, 2H), 3.70 (t, 2H), 2.35 (m, 1H), 0.58-0.53 (m, 4H).

Intermediate Example 17 N-(1H-pyrazol-4-yl)acetamide

Acetic anhydride (0.7 ml, 8.433 mmol.) was added dropwise at 0° C. to1H-pyrazol-4-amine (0.7 g, 8.433 mmol). The mixture was stirred for 30min at RT and quenched by the addition of crushed ice. The mixture wasextracted with ethyl acetate The combined organic layer was washed withwater, brine and dried over sodium sulphate. The solvent was distilledoff to afford the product in 54% yield. (0.6 g). LC-MS (ESI): Calculatedmass: 125.0; Observed mass 126.0 [M+H]⁺ (rt: 0.115 min).

Intermediate Example 18 2-(1H-1, 2, 4-triazol-1-yl) acetic acid a) Ethyl2-(1H-1, 2,4-triazol-1-yl) acetate

To a solution of 1H-1, 2, 4-triazol (2 g, 29.9 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (12.3 g, 88.9 mmol, 3 eq.) and ethyl 2-bromoacetate (4.8 g,29.9 mmol, 1 eq). The mixture was stirred at RT for 16 h. The mixturewas quenched and extracted as in Intermediate Example 5(a). The solventwas distilled off to give the product in 65% yield (3 g). LC-MS (ESI):Calculated mass: 155.0; Observed mass: 156.1 [M+H]⁺ (rt: 0.113 min).

b) 2-(1H-1, 2, 4-triazol-1-yl) acetic acid

The solution of the compound of Intermediate Example 18(a) (3 g, 19.35mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h and concentratedon vacuum pump. The mixture was quenched and extracted as inIntermediate Example 15(b). The solvent was distilled off to afforddesired product in 62% yield (1.5 g). LC-MS (ESI): Calculated mass:127.0; Observed mass: 128.0 [M+H]⁺ (rt: 0.24 min).

Intermediate Example 19 a) Ethyl 2-(pyrrolidin-1-yl) acetate

To a solution of pyrrolidine (1.2 g, 16.3 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (1.73g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h andquenched and extracted as in Intermediate Example 5(a). The solvent wasdistilled off to afford the product in 80% yield (2 g). LC-MS (ESI):Calculated mass: 157.2; Observed mass 158.1 [M+H]⁺ (rt: 0.2 min).

b) 2-(Pyrrolidin-1-yl) acetic acid

The solution of ethyl 2-(pyrrolidin-1-yl)acetate (2 g, 12.7 mmol, 1.0eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture wasconcentrated and quenched and extracted as in Intermediate Example15(b). The solvent was distilled off to afford the product in 91% yield(1.5 g). LC-MS (ESI): Calculated mass: 129.1; Observed mass 130.1 [M+H]⁺(rt: 0.26 min).

Intermediate Example 20 2-Morpholinoacetic acid a) Ethyl2-morpholinoacetate

To a solution of morpholine (1.4 g, 16.3 mmol, 1.0 eq) in DMF were addedK₂CO₃ (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (4.07 g,24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenchedand extracted as in Intermediate Example 5(a). The solvent was distilledoff to afford the product in 71.4% yield (2 g). LC-MS (ESI): Calculatedmass: 173.2; Observed mass: 174.0 [M+H]⁺ (rt: 0.20 min).

b) 2-Morpholinoacetic acid

The solution of ethyl 2-morpholinoacetate (1 g, 57.8 mmol, 1.0 eq) in 8N HCl was stirred at 95° C. for 16 h. The mixture was concentrated andquenched and extracted as in Intermediate Example 15(b). The solvent wasdistilled off to afford the product in 96.3% yield (0.8 g). LC-MS (ESI):Calculated mass: 145.16; Observed mass: 146.3 [M+H]⁺ (rt: 0.21 min).

Intermediate Example 21 2-(Piperidin-1-yl) acetic acid a) Ethyl2-(piperidin-1-yl) acetate

To a solution of piperidine (3.4 g, 40.7 mmol, 1.0 eq) in DMF were addedK₂CO₃ (14 g, 101.0 mmol, 2.5 eq.) and ethyl 2-chloroacetate (4.83 ml,48.9 mmol, 1.2 eq). The mixture was stirred at RT for 16 h. The mixturewas quenched and extracted as in Intermediate Example 5(a). The solventwas distilled off to give the product in 72% yield (5 g). LC-MS (ESI):Calculated mass: 171.1; Observed mass 172.3 [M+H]⁺ (rt: 0.1 min).

b) 2-(Piperidin-1-yl) acetic acid

The solution of ethyl 2-(piperidin-1-yl)acetate (1 g, 5.84 mmol, 1.0 eq)in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentratedand quenched and extracted as in Intermediate Example 15(b). The solventwas distilled off to afford the product in 95% yield (0.8 g). LC-MS(ESI): Calculated mass: 143.1; Observed mass 144.4 [M+H]⁺ (rt: 0.21min).

Intermediate Example 22 2-(3, 5-Dimethylpiperazin-1-yl) acetic acid a)Ethyl 2-(3, 5-dimethylpiperazin-1-yl) acetate

To a solution of 2, 6-dimethylpiperazine (500 mg, 4.378 mmol, 1.0 eq) inTHF were added K₂CO₃ (1.2 g, 8.75 mmol, 2.2 eq.) and ethyl2-bromoacetate (731 mg, 4.378 mmol, 1 eq). The mixture was stirred at RTfor 4 h and then quenched and extracted as in Intermediate Example 5(a).The solvent was distilled off to afford the product in 34% yield (0.3g). LC-MS (ESI): Calculated mass: 200.0; Observed mass: 201.0 [M+H]⁺(rt: 0.102 min).

b) 2-(3, 5-Dimethylpiperazin-1-yl) acetic acid

The solution of the compound of Intermediate Example 22(a) (300 mg, 1.5mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture wasconcentrated and quenched and extracted as in Intermediate Example15(b). The solvent was distilled off to afford the product in 96% yield(250 mg). LC-MS (ESI): Calculated mass: 172.0; Observed mass: 173.1[M+H]⁺ (rt: 0.094 min).

Intermediate Example 23 2-(4-(tert-Butoxycarbonyl) piperazin-1-yl)acetic acid a) tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (2.9 g, 10.7 mmol,1.0 eq) in THF were added potassium carbonate (2.96 g, 21.0 mmol, 2 eq)and ethyl 2-bromoacetate (1.58 g, 10.7 mmol, 1 eq). The mixture wasstirred at RT for 16 h. The mixture was quenched and extracted as inIntermediate Example 5(a). The solvent was distilled off to afford theproduct in 51% yield (1.5 g).

b) 2-(4-(tert-Butoxycarbonyl) piperazin-1-yl) acetic acid

To a solution of the compound of Intermediate Example 23(a) (1.5 g, 5.51mmol) in methanol (10 ml) was added aqueous solution of NaOH (0.8 g,22.0 mmol, 4 eq). The mixture was stirred at RT for 2 h. The mixture wasconcentrated and extracted as in Intermediate Example 5(c). The solventwas distilled off to give the product in 76% yield (1 g). LC-MS (ESI):Calculated mass: 244.29; Observed mass: 145.1 [M-Boc+H]⁺ (rt: 0.102min).

Intermediate Example 24 a) Ethyl 2-(4-ethylpiperazin-1-yl)acetate

To a solution of 1-ethylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (3 g, 21.927 mmol, 2.5 eq.) and ethyl 2-bromoacetate (2.19g, 13.156 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h. Themixture was quenched and extracted as in Intermediate Example 5(a). Thesolvent was distilled off to afford the product in 76.4% yield (1.3 g).

b) 2-(4-Ethylpiperazin-1-yl)acetic acid

The solution of ethyl 2-(4-ethylpiperazin-1-yl)acetate (1.3 g, 6.50mmol, 1.0 eq) in 8 N HCl stirred at 95° C. for 16 h. The mixture wasconcentrated on vacuum pump, and quenched and extracted as inIntermediate Example 15(b). The solvent was distilled off to afford theproduct in 54.5% yield (0.6 g).

Intermediate Example 25 1-Isopropyl-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole a) 4-Bromo-1-isopropyl-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (5 g, 34.24 mmol, 1.0 eq) in DMFwere added K₂CO₃ (11.83 g, 85.60 mmol, 2.5 eq.) and 2-bromopropane (6.31g, 51.36 mmol, 1.5 eq.) The mixture was stirred at RT for 12 h. Themixture was quenched and extracted as in Intermediate Example 5(a). Thesolvent was distilled off to afford the product in 76.9% yield (5.0 g).

b) 1-Isopropyl-4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole

To a (N₂ bubbling) solution of 4-bromo-1-isopropyl-1H-pyrazole (1.5 g,7.894 mmol) in 1,4 dioxane (15 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.0 g,11.84 mmol, 1.5 eq.), Pd(dppf)Cl₂ (0.644 g, 0.784 mmol, 0.1 eq.) andpotassium acetate (1.93 g, 19.73 mmol, 2.5 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off and the residuewas purified by column chromatography (60-120 silica gel, 15% ethylacetate in hexane) to yield the product in 66.6% yield (1.2 g). LC-MS(ESI): Calculated mass: 236.17; Observed mass: 237.1 [M+H]⁺ (rt: 1.4min).

Intermediate Example 26 2-(Piperidin-1-yl) acetic acid a) Ethyl2-(piperidin-1-yl) acetate

To a solution of piperidine (1.5 g, 17.61 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (6.08 g, 44.02 mmol, 2.5 eq.) and ethyl 2-chloroacetate(3.23 g, 26.42 mmol, 1.5 eq.). The mixture was stirred at RT for 12 hand quenched and extracted as in Intermediate Example 5(a). The solventwas distilled off to afford the product in 80% yield (2.4 g). LC-MS(ESI): Calculated mass: 171.1; Observed mass 172.3 [M+H]⁺ (rt: 0.1-0.2min).

b) 2-(Piperidin-1-yl) acetic acid

The solution of ethyl 2-(piperidin-1-yl) acetate (2.4 g, 14.0 mmol, 1.0eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture wasconcentrated on vacuum pump and quenched and extracted as inIntermediate Example 15(b). The solvent was distilled off to afford theproduct in 60% yield (1.2 g). LC-MS (ESI): Calculated mass: 143.1;Observed mass 144.4 [M+H]⁺ (rt: 0.21 min).

Intermediate Example 27 2-Morpholinoacetic acid a) Ethyl2-morpholinoacetate

To a solution of morpholine (0.5 g, 5.739 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (1.98 g, 14.34 mmol, 2.5 eq.) and ethyl 2-chloroacetate(1.05 g, 8.60 mmol, 1.5 eq.). The mixture was stirred at RT for 12 h.The mixture was quenched and extracted as in Intermediate Example 5(a).The solvent was distilled off to afford the product in 73.9% yield(0.735 g). LC-MS (ESI): Calculated mass: 173.21; Observed mass 174.0[M+H]⁺ (rt: 0.1-0.4 min).

b) 2-Morpholinoacetic acid

The solution of ethyl 2-morpholinoacetate (0.73 g, 4.24 mmol, 1.0 eq) in8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated onvacuum pump and quenched and extracted as in Intermediate Example 15(b).The solvent was distilled off to afford the product in 60% yield (0.37g). LC-MS (ESI): Calculated mass: 145.1; Observed mass 146.3 [M+H]⁺ (rt:0.28 min).

Intermediate Example 28 2-(Pyrrolidin-1-yl) acetic acid a) Ethyl2-(pyrrolidin-1-yl) acetate

To a solution of pyrrolidine (0.9 g, 12.65 mmol, 1.0 eq) in DMF wereadded K₂CO₃ (4.37 g, 31.62 mmol, 2.5 eq.) and ethyl 2-chloroacetate(2.32 g, 18.98 mmol, 1.5 eq.). The mixture was stirred at RT for 12 h.The mixture was quenched and extracted as in Intermediate Example 5(a).The solvent was distilled off to afford the product in 94.7% yield (1.8g). LC-MS (ESI): Calculated mass: 157.2; Observed mass 158.1 [M+H]⁺ (rt:0.2-0.3 min).

b) 2-(Pyrrolidin-1-yl) acetic acid

The solution of ethyl 2-(pyrrolidin-1-yl) acetate (1.8 g, 11.95 mmol,1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture wasconcentrated on vacuum pump and quenched and extracted as inIntermediate Example 15(b). The solvent was distilled off to afford theproduct in 54% yield (1.4 g). LC-MS (ESI): Calculated mass: 129.1;Observed mass 130.1 [M+H]⁺ (rt: 0.26 min).

Intermediate Example 29 2-Methyl-4-(4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) butan-2-ol a)4-Bromo-2-methylbutan-2-ol

To a solution of methyl 3-bromopropanoate (5.0 g, 29.94 mmol, and 1.0eq) in dry THF was added methyl magnesium bromide at 0° C. The mixturewas stirred at RT for 16 h and quenched and extracted as in IntermediateExample 5(c). The solvent was distilled off to afford the crude residuewhich was purified by column chromatography (60-120 silica gel, 50%ethyl acetate in hexane). Yield 48.9% (2.4 g). LC-MS (ESI): Calculatedmass: 167.0; Observed mass 167.1[M+H]⁺ (rt: 0.8-1.0 min).

b) 4-(4-Bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol

To a solution of 4-bromo-1H-pyrazole (1 g, 6.84 mmol, 1.0 eq) in DMFwere added K₂CO₃ (2.3 g, 17.1 mmol, 2.5 eq.) and4-bromo-2-methylbutan-2-ol (1.7 g, 10.27 mmol, 1.5 eq.). The mixture wasstirred at RT for 16 h. The mixture was quenched and extracted as inIntermediate Example 5(a). The solvent was distilled off to afford theproduct in 60% yield (0.9 g). LC-MS (ESI): Calculated mass 233.0;Observed mass 235.0. [M+H]⁺ (rt: 0.64 min).

c) 2-Methyl-4-(4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) butan-2-ol

To a degassed (N₂ bubbling) solution of the compound of IntermediateExample 29(b) (0.5 g, 2.16 mmol) in 1,4-dioxane (5 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.824 g,3.24 mmol, 1.5 eq.), Pd(dppf)Cl₂ (0.1766 g, 0.216 mmol, 0.1 eq.) andpotassium acetate (0.529 g, 5.40 mmol, 2.5 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off which waspurified by column chromatography (60-120 silica gel, 15% ethyl acetatein hexane) to yield the product in 49.6% yield (0.3 g). LC-MS (ESI):Calculated mass: 280.1; Observed mass: 281.2 [M+H]⁺ (rt: 0.8 min).

Intermediate Example 30 tert-Butyl 3-(4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate a)tert-Butyl 3-(methylsulfonyl) pyrrolidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g,5.34 mmol, 1.0 eq) in DCM (10 ml) were added TEA (1.08 g, 10.68 mmol,2.0 eq) and DMAP (65 mg, 0.53 mmol). The mixture was stirred at RT for15 min. Then methanesulfonyl chloride (0.730 g 6.41 mmol 1.2 eq) wasadded and the mixture was stirred for overnight. The mixture wasquenched and extracted as in Intermediate Example 5(a). The solvent wasdistilled off to afford the product in 71.4% yield (1.0 g).

b) tert-Butyl 3-(4-bromo-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

To a solution of 4-bromo-1H-pyrazole (0.65 g, 4.42 mmol) in DMF wereadded sodiumhydride at 0° C. (0.159 g, 6.6 mmol, 1.5 eq.) and thecompound of Intermediate Example 30(a) (1.1 g, 4.42 mmol, 1.0 eq.). Themixture was stirred at RT for 16 h and quenched and extracted as inIntermediate Example 5(a). The solvent was distilled off to afford thecrude residue which was purified by column chromatography (60-120 silicagel, 1% methanol in DCM) to yield the product in 61.5% yield (0.85 g).

c) tert-Butyl 3-(4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

To a degassed (N₂ bubbling) solution of the compound of IntermediateExample 30(b) (0.850 g, 2.68 mmol) in 1,4-dioxane (10 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.819 g,3.22 mmol, 1.2 eq.), Pd(dppf)Cl₂ (0.218 g, 0.268 mmol, 0.1 eq.) andpotassium acetate (0.788 g, 8.04 mmol, 3.0 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off to give theproduct in 84.5% yield (0.82 g). LC-MS (ESI): Calculated mass: 363.2;Observed mass: 364.2 [M+H]⁺ (rt: 1.73 min).

Intermediate Example 31 4-(4-Fluoro-3-nitrophenyl)-1-methyl-1H-pyrazol

A solution of 4-bromo-1-fluoro-2-nitrobenzene (2 g, 9.095 mmol) in1,4-dioxane (20 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.27 g, 10.91 mmol, 1.2 eq.) and aqueous sodium carbonate (2.89 g,27.27 mmol, 3.0 eq.) were added and the mixture was degassed for another15 min. Pd(PPh₃)₂Cl₂ (0.638 g, 0.909 mmol, 0.1 eq.) was addedsequentially and the mixture was further degassed for 15 min and thenheated at 90° C. for 2 h. The mixture was quenched and extracted as inIntermediate Example 5(c). The solvent was distilled off to afford thecrude residue which was purified by column chromatography (60-120 silicagel, 40-50% ethyl acetate in hexane) to yield the product in 79% yield(1.6 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.32-8.26 (m, 2H), 8.0-7.97 (m,2H), 7.62-7.55 (m, 1H).

Intermediate Example 321-Cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolea) 1-Cyclopentyl-4-iodo-1H-pyrazole

To a solution of 4-iodo-1H-pyrazole (5 g, 25.78 mmol, 1.0 eq.) in DMF(25 ml) were added K₂CO₃ (8.908 g, 64.45 mmol, 2.5 eq.) andbromocyclopentane (4.96 g, 33.51 mmol, 1.3 eq.). The mixture was stirredat RT for 12 h. The mixture was quenched and extracted as inIntermediate Example 5(a). The solvent was distilled off to give theproduct in 89.5% yield. ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 7.45(s, 1H), 4.66-4.62 (m, 1H), 2.17-2.02 (m, 1H), 2.00-1.96 (m, 2H),1.93-1.78 (m, 2H), 1.73-1.67 (m, 2H). LC-MS (ESI): Calculated mass: 262;Observed mass: 263 [M+H]⁺ (rt: 1.57 min).

b)1-Cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a degassed (N₂ bubbling) solution of 1-cyclopentyl-4-iodo-1H-pyrazole(6.0 g, 22.90 mmol) in DMSO (60 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.312 g,34.35 mmol, 1.5 eq.), Pd(dppf)Cl₂ (0.529 g, 0.45 mmol, 0.02 eq.) andpotassium acetate (4.494 g, 45.80 mmol, 2.0 eq.) using the procedure ofIntermediate Example 1(b). The solvent was distilled off which waspurified by column chromatography (60-120 silica gel, 15% ethyl acetatein hexane) to yield the product in 48% yield (2.89 g). ¹H NMR (300 MHz,CDCl₃): δ 7.77 (s, 1H), 7.72 (s, 1H), 4.65 (m, 1H), 2.17-2.02 (m, 1H),2.00-1.96 (m, 2H), 1.93-1.78 (m, 2H), 1.73-1.67 (m, 2H), 1.30-1.24 (m,12H). LC-MS (ESI): Calculated mass: 262; Observed mass: 262.92 [M+H]⁺(rt: 1.54 min).

Intermediate Example 33 tert-Butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-carbamate

To a solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.33 g,1.5 mmol) in CH₂Cl₂ (5 ml) at 0° C. were added Boc₂O (0.33 g, 1.5 mmol,1 eq.) and Et₃N (0.62 ml, 4.5 mmol, 3 eq.). The mixture was stirred atRT for 1 h and then quenched and extracted as in Intermediate Example5(a). The solvent was distilled off to afford the crude product (0.48g).

Example 1N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamidea) 1-Bromo-3,5-dinitrobenzene

To a solution of 1,3-dinitrobenzene (25 g, 0.149 mol) in concentratedsulfuric acid (100 ml) at 0° C. was added1,3-dibromo-5,5-dimethylhydantoin (31.75 g, 0.111 mol, 0.75 eq)portionwise over a period of 30 min. The mixture was stirred for 12 atRT and quenched by the addition of crushed ice. The precipitate formedwas filtered and was washed repeatedly with water to obtain white solid.The solid was dried under vacuum to give the product in 87% yield (32g).

b) 3-Bromo-5-nitroaniline

To a solution of 1-bromo-3,5-dinitrobenzene (20 g, 80.97 mmol) in aceticacid (120 ml) at 90° C. was added iron powder (11.3 g, 202.4 mmol, 2.5eq) slowly portionwise over a period of 30 min (caution: highlyexothermic reaction). After completion of the addition, the mixture wasquenched by the addition of crushed ice. The precipitate formed wasfiltered and was washed with cold water to obtain orange solid. Thesolid was dried under vacuum to give the product in 80% yield (14 g). ¹HNMR (300 MHz, CDCl₃): δ 10.55 (br s, 2H), 8.46 (s, 1H), 8.19 (s, 1H),8.02 (s, 1H).

c) N-(3-Bromo-5-nitrophenyl)acetamide

Acetic anhydride (14 ml) was added dropwise at 0° C. to3-bromo-5-nitroaniline (14 g, 64.5 mmol). The mixture was stirred for 30min at RT and then quenched by the addition of crushed ice. Theprecipitate formed was filtered and washed with cold water to obtainoff-white solid. The solid was dried under vacuum to give the product in78% yield (13 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.54 (br s, 1H), 8.45(s, 1H), 8.2 (s, 1H), 8.03 (s, 1H), 2.11 (s, 3H).

d) N-(2′,4′-difluoro-5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.86 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.2,4-Difluorophenylboronic acid (0.727 g, 4.63 mmol, 1.2 eq.) was addedand the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.627 g,0.769 mmol, 0.2 eq.) and aqueous sodium carbonate (1.22 g, 11.5 mmol,3.0 eq.) were added sequentially and the mixture was further degassedfor 5 min and then heated at 90° C. for 2 h. The mixture was quenchedwith water and extracted with ethyl acetate (3×50 ml). The combinedorganic layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off under reduced pressure and thecrude residue was purified by column chromatography (60-120 silica gel,30% ethyl acetate in hexane) to give the product in 80% yield (0.9 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.63 (s, 1H), 8.7-8.69 (m, 1H), 8.16 (d,1H), 8.04 (s, 1H), 7.8-7.67 (m, 1H), 7.53 (m, 1H), 7.34 (m, 1H), 2.19(s, 3H).

e) N-(5-amino-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of N-(2′,4′-difluoro-5-nitrobiphenyl-3-yl)acetamide (4 g,13.7 mmol) in methanol (30 ml) and ethyl acetate (15 ml) was added 10%Pd/C (400 mg, 0.1 eq.) and the reaction vessel was purged with nitrogengas for 5 min. The mixture was then hydrogenated with H₂ balloon for 12h. The mixture was filtered through a pad of celite and the filtrate wasconcentrated under reduced pressure to afford the compound in 89% yield(3.2 g). ¹H NMR (300 MHz, DMSO-d₆): δ 9.77 (br s, 1H), 7.46-7.42 (m,1H), 7.35-7.28 (m, 1H), 7.2-7.15 (m, 1H), 6.99 (br s, 1H), 8.86 (d, 1H),6.39 (d, 1H), 5.45 (br s, 2H), 2.02 (s, 3H).

f)N-(5-(4-bromo-2-nitrophenylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide

A solution of N-(5-amino-2′,4′-difluorobiphenyl-3-yl)acetamide (3.0 g,11.44 mmol), 4-bromo-1-fluoro-2-nitrobenzene (2.52 g, 11.44 mmol, 1.0eq.) and potassium fluoride (0.663 g, 11.44 mmol, 1.0 eq.) in DMF washeated at 130° C. for 5 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off under reduced pressure andthe crude residue was purified by column chromatography (60-120 silicagel, 40% ethyl acetate in hexane) to afford the product in 45% yield(2.4 g).

g)N-(5-(2-amino-4-bromophenylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution ofN-(5-(4-bromo-2-nitrophenylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide(3.2 g, 6.92 mmol) in THF (30 ml) were added a solution of ammoniumchloride (3.7 g, 69.22 mmol, 10 eq.) in water (15 ml) and zinc (4.53 g,69.22 mmol, 10 eq.). The mixture was stirred at RT for 6 h and filtered.The filtrate was diluted with water and extracted as in Example 1(d).The solvent was distilled off under reduced pressure to afford theproduct in 87% yield (2.6 g).

h)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)-acetamide

A mixture of the compound of Example 1(g) (2.6 g, 6.01 mmol) and formicacid (10 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off under reduced pressure and the crude was dissolved inethyl acetate. The ethyl acetate layer was washed with water, brine anddried over sodium sulphate. The solvent was distilled off under reducedpressure to afford the product in 60% yield (1.6 g). ¹H NMR (300 MHz,DMSO-d₆): δ 10.41 (s, 1H), 8.72 (s, 1H), 8.02 (d, 2H), 7.82 (s, 1H),7.75-7.66 (m, 2H), 7.53-7.41 (m, 3H), 7.27 (m, 1H), 2.11 (s, 3H).

i)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

A solution of the compound of Example 1(h) (1.5 g, 3.39 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.847 g, 4.07 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (0.553 g, 0.678 mmol, 0.2 eq.) and aqueoussodium carbonate (1.08 g, 10.18 mmol, 3.0 eq.) were added following theprocedure described in Example 1(d). The crude residue of the productwas purified by column chromatography (60-120 silica gel, 80% ethylacetate in hexane) to afford the product in 67% yield (1.0 g). ¹H NMR(300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.64 (s, 1H), 8.2 (1H, s), 8.07 (s,1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.8-7.68 (m, 2H), 7.6-7.45 (m, 4H),7.27 (t, 1H), 3.88 (s, 3H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass:443.45; Observed mass: 444.1 [M+H]⁺ (rt: 1.2 min).

Example 2N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)methanesulfonamidea)2′,4′-Difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-amine

To a solution ofN-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo-[d]imidazol-1-yl)biphenyl-3-yl)acetamideof Example 1 (1.0 g, 2.26 mmol) in ethanol (10 ml) was added aqueoussolution of NaOH (800 mg, 20 mmol, 8.9 eq.) and the mixture was heatedat 85° C. for 5 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off under reduced pressure to afford theproduct in 66% yield (0.6 g). LC-MS (ESI): Calculated mass: 401.41;Observed mass: 402.1 [M+H]⁺ (rt: 1.198 min).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 2(a) (50 mg, 0.125 mmol) in DCMwas added pyridine (20 mg, 0.249 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (17 mg, 0.15 mmol, 1.2 eq.). The mixture wasstirred for 1 h, quenched with water and extracted with DCM (3×50 ml).The combined organic layer was washed with water, brine and dried oversodium sulphate. The solvent was distilled off under reduced pressureand the crude residue was purified by preparative HPLC to give theproduct in 33% yield (20 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.26 (s,1H), 8.66 (s, 1H), 8.2 (s, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.75-7.67(m, 2H), 7.57 (t, 3H), 7.45-7.43 (m, 2H), 7.29-7.25 (m, 1H), 3.87 (s,3H), 3.17 (s, 3H); LC-MS (ESI): Calculated mass: 479.5; Observed mass:480.2 [M+H]⁺ (rt: 1.34 min).

Example 3N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 1 using theprocedures of Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 10.29 (s, 1H),8.84 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.78-7.62 (m,3H), 7.57 (br s, 2H), 7.48-7.43 (m, 2H), 7.29-7.25 (m, 1H), 3.88 (s,3H), 3.29 (quartet, 2H), 1.25 (t, 3H); LC-MS (ESI): Calculated mass:493.53; Observed mass: 494.2 [M+H]⁺ (rt: 1.41 min).

Example 4N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 1 using theprocedures of Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 10.29 (s, 1H),8.81 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.75-7.56 (m,5H), 7.48-7.43 (m, 2H), 7.27 (m, 1H), 3.88 (s, 3H), 3.48-3.44 (m, 1H),1.3 (d, 6H); LC-MS (ESI): Calculated mass: 507.55; Observed mass: 508.2[M+H]⁺ (rt: 1.47 min).

Example 5N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 1 using theprocedures of Example 2 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.88 (s, 1H), 8.23 (s, 1H), 8.0 (s, 1H),7.96 (s, 1H), 7.76-7.64 (m, 3H), 7.6 (s, 2H), 7.5-7.46 (m, 2H), 7.3-7.25(m, 1H), 3.88 (s, 3H), 2.88-2.85 (m, 1H), 1.02-1.0 (m, 4H); LC-MS (ESI):Calculated mass: 505.54; Observed mass: 506.1 [M+H]⁺ (rt: 1.517 min).

Example 6N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)cyclopentanesulfonamide

The compound was prepared from the compound of Example 1 using theprocedures of Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 10.25 (s, 1H),8.96 (s, 1H), 8.24 (s, 1H), 8.0 (s, 1H), 7.97 (s, 1H), 7.77-7.66 (m,3H), 7.6-7.59 (m, 2H), 7.49 (m, 1H), 7.46-7.43 (m, 1H), 7.3-7.25 (m,1H), 3.88 (s, 3H), 3.83-3.78 (m, 1H), 1.99-1.93 (m, 4H), 1.69-1.64 (m,2H), 1.63-1.52 (m, 2H); LC-MS (ESI): Calculated mass: 533.59; Observedmass: 534.3 [M+H]⁺ (rt: 1.57 min).

Example 7N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)benzenesulfonamide

The compound was prepared from the compound of Example 1 using theprocedures of Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 8.57 (s, 1H), 8.21(s, 1H), 7.96-7.95 (m, 2H), 7.88-7.86 (m, 2H), 7.72-7.61 (m, 4H),7.57-7.55 (m, 2H), 7.5 (br s, 1H), 7.45-7.32 (m, 4H), 7.26-7.22 (m, 1H),3.88 (s, 3H); LC-MS (ESI): Calculated mass: 541.57; Observed mass: 542.1[M+H]⁺ (rt: 1.642 min).

Example 8N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

A solution of compound of Example 1(h) (7 g, 15.83 mmol) in1,2-dimethoxyethane (200 ml) was degassed by N₂ bubbling for 5 min.N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamineof Intermediate Example 1 (6.3 g, 23.74 mmol, 1.5 eq.) was added and themixture was degassed for another 5 min. Pd(PPh₃)₄ (1.83 g, 1.583 mmol,0.1 eq.) and aqueous sodium carbonate (5.03 g, 47.5 mmol, 3.0 eq.) wereadded following the procedure of Example 1(d). The crude residue of theproduct was purified by column chromatography (neutral alumina, 80%ethyl acetate in hexane) to give the product in 19% yield (1.5 g). ¹HNMR (300 MHz, DMSO-d₆): δ; 10.45 (s, 1H), 8.8 (s, 1H), 8.35 (s, 1H),8.15 (s, 2H), 8.05 (s, 1H), 7.6-7.7 (m, 4H), 7.4-7.55 (m, 2H), 7.2-7.3(m, 1H), 4.56 (t, 2H), 3.65-3.63 (m, 2H), 2.85 (s, 6H), 2.12 (s, 3H);LC-MS (ESI): Calculated mass: 500.54; Observed mass: 501.2 [M+H]⁺ (rt:0.277 min).

Example 9N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamidea)5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-amine

To a solution of the compound of Example 8 (1.5 g, 3.0 mmol) in ethanol(30 ml) was added aqueous solution of NaOH (1.5 g, 37.5 mmol, 12.5 eq.)and the mixture was heated at 100° C. for 4 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was distilled off toafford the product in 58% yield (0.8 g).

b)N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 9(a) (200 mg, 0.436 mmol) inDCM was added pyridine (69 mg, 0.872 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (75 mg, 0.654 mmol, 1.5 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the crude residue was purified bypreparative HPLC to give the product in 13% yield (30 mg). ¹H NMR (300MHz, DMSO-d₆): δ 8.66 (s, 1H), 8.26 (s, 1H), 7.99 (d, 1H), 7.96 (s, 1H),7.81-7.7 (m, 2H), 7.68 (s, 1H), 7.62-7.57 (m, 3H), 7.5-7.44 (m, 2H),7.3-7.25 (m, 1H), 4.23 (t, 2H), 3.18 (s, 3H), 2.75-2.73 (m, 2H), 2.12(s, 6H); LC-MS (ESI): Calculated mass: 536.6; Observed mass: 537.3[M+H]⁺ (rt: 0.26 min).

Example 10N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 8 using theprocedures of Example 9. ¹H NMR (300 MHz, DMSO-d₆): δ 10.35 (s, 1H),9.2-9.4 (br s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H),7.6-7.8 (m, 2H), 7.6 (s, 2H), 7.4-7.5 (m, 2H), 7.2-7.3 (m, 1H), 4.55 (t,2H), 3.65-3.63 (m, 2H), 3.3 (quartet, 2H), 2.85 (s, 6H), 1.26 (t, 3H);LC-MS (ESI): Calculated mass: 550.62; Observed mass: 551.2 [M+H]⁺ (rt:0.365 min).

Example 11N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 8 using theprocedures of Example 9. ¹H NMR (300 MHz, CD₃OD): δ 8.5 (s, 1H), 8.1 (s,1H), 7.9-7.95 (d, 2H), 7.55-7.7 (m, 5H), 7.45-7.5 (m, 2H), 7.05-7.1 (m,2H), 4.32 (t, 2H), 3.44-3.39 (m, 1H), 2.85 (t, 2H), 2.3 (s, 6H), 1.4 (d,6H); LC-MS (ESI): Calculated mass: 564.65; Observed mass: 565.2 [M+H]⁺(rt: 0.507 min).

Example 12N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)acetamide

The compound was prepared using the procedures of Example 8 using thecompound of Intermediate Example 2. ¹H NMR (300 MHz, DMSO-d₆): δ 10.43(s, 1H), 8.82 (s, 1H), 8.35 (s, 1H), 8.13 (s, 2H), 8.05 (s, 1H),7.79-7.73 (m, 3H), 7.67-7.63 (m, 1H), 7.51-7.44 (m, 2H), 7.31-7.27 (m,1H), 4.6 (t, 2H), 3.93-3.88 (m, 4H), 3.67-3.63 (m, 4H), 3.82-3.78 (m,2H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 542.58; Observed mass:543.2 [M+H]⁺ (rt: 0.24 min).

Example 13N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 12 using theprocedures of Example 9. ¹H NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.8(s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.7-7.8 (m, 2H),7.6-7.7 (m, 1H), 7.55-7.6 (m, 2H), 7.4-7.5 (m, 2H), 7.25-7.35 (m, 1H),4.59 (t, 2H), 4.0 (m, 4H), 3.82-3.78 (m, 2H), 3.5 (m, 4H), 3.18 (s, 3H);LC-MS (ESI): Calculated mass: 578.63; Observed mass: 579.2 [M+H]⁺ (rt:0.383 min).

Example 14N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 12 using theprocedures of Example 9. ¹H NMR (300 MHz, DMSO-d₆): δ 10.35 (s, 1H),8.85 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.77-7.68 (m,3H), 7.58 (s, 2H), 7.48-7.45 (m, 2H), 7.31-7.27 (m, 1H), 4.59 (t, 2H),4.0-3.92 (m, 4H), 3.82-3.78 (m, 2H), 3.5-3.41 (m, 4H), 3.29 (quartet,2H), 1.25 (t, 3H); LC-MS (ESI): Calculated mass: 592.66; Observed mass:593.2 [M+H]⁺ (rt: 0.419 min).

Example 15N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 12 using theprocedures of Example 9. ¹H NMR (300 MHz, CD₃OD): δ 8.5 (s, 1H), 8.1 (s,1H), 7.93 (s, 1H), 7.9 (s, 1H), 7.6-7.7 (m, 4H), 7.5 (s, 2H), 7.1-7.15(m, 2H), 4.33 (t, 2H), 3.67 (t, 4H), 3.46-3.39 (m, 1H), 2.85 (t, 2H),2.52 (t, 4H), 1.4 (d, 6H); LC-MS (ESI): Calculated mass: 606.69;Observed mass: 607.3 [M+H]⁺ (rt: 0.62 min).

Example 16N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 12 using theprocedures of Example 9 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 8.6 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H),7.74-7.65 (m, 2H), 7.59-7.55 (m, 1H), 7.45-7.38 (m, 2H), 7.28-7.24 (m,4H), 4.24 (t, 2H), 3.56 (t, 4H), 2.75 (t, 2H), 2.67-2.64 (m, 1H), 2.42(t, 4H), 0.91-0.88 (m, 4H); LC-MS (ESI): Calculated mass: 604.67;Observed mass: 605.4 [M+H]⁺ (rt: 0.68 min).

Example 17N-(2′,4′-difluoro-5-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamidea)N-(2′,4′-difluoro-5-(4-iodo-2-nitrophenylamino)biphenyl-3-yl)acetamide

A solution of the compound of Example 1(e) (4.6 g, 17.54 mmol),1-fluoro-4-iodo-2-nitrobenzene of Intermediate Example 3 (4.683 g, 17.54mmol, 1.0 eq.) and potassium fluoride (1.22 g, 21.05 mmol, 1.2 eq.) inDMF was heated at 130° C. for 5 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and thecrude residue was purified by column chromatography (60-120 silica gel,50% ethyl acetate in hexane) to give the product in 76% yield (6.8 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.15 (br s, 1H), 9.41 (s, 1H), 8.35 (d,1H), 7.78 (dd, 1H), 7.66-7.54 (m, 3H), 7.39 (m, 1H), 7.22 (m, 1H),7.14-7.11 (m, 2H), 2.06 (s, 3H).

b)N-(5-(2-amino-4-iodophenylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 17(a) (3.0 g, 5.89 mmol) in THF(30 ml) were added a solution of ammonium chloride (1.26 g, 23.56 mmol,4 eq.) in water (5 ml) and zinc (1.54 g, 23.56 mmol, 4 eq.). The mixturewas stirred at RT for 0.5 h and filtered. The filtrate was diluted withwater and extracted as in Example 1(d). The solvent was distilled off toafford the product in 77% yield (2.18 g). ¹H NMR (300 MHz, DMSO-d₆): δ9.85 (br s, 1H), 7.44 (quartet, 1H), 7.36-7.31 (m, 2H), 7.19-7.14 (m,2H), 7.07 (s, 1H), 7.02 (s, 1H), 6.82 (s, 2H), 6.53 (br s, 1H), 5.03 (brs, 2H), 2.0 (s, 3H).

c)N-(2′,4′-difluoro-5-(5-iodo-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

A mixture of the compound of Example 17(b) (2.18 g, 4.55 mmol) andformic acid (10 ml) was heated at 100° C. for 30 min. The formic acidwas distilled off and the crude was dissolved in ethyl acetate. Theethyl acetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 47%yield (1.05 g).

d)N-(2′,4′-difluoro-5-(5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

A solution of the compound of Example 17(c) (0.7 g, 1.43 mmol) inDMF-Et₃N (1:1; 20 ml) was degassed by N₂ bubbling for 15 min. Pd(PPh₃)₄(0.165 g, 0.143 mmol, 0.1 eq.), copper(I) iodide (0.027 g, 0.143 mmol,0.1 eq.) and ethynyltrimethylsilane (0.4 ml, 2.86 mmol, 2 eq.) wereadded sequentially and the mixture was stirred for 12 h at RT. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the crude residue was purified by columnchromatography (60-120 silica gel, 60% ethyl acetate in hexane) to givethe product in 68% yield (0.45 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42(s, 1H), 8.79 (br s, 1H), 8.03 (s, 1H), 7.89-7.84 (m, 2H), 7.78-7.7 (m,2H), 7.51-7.41 (m, 3H), 7.29-7.24 (m, 1H), 2.12 (s, 3H), 0.23 (s, 9H).

e)N-(5-(5-ethynyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)-acetamide

To a solution of the compound of Example 17(d) (0.41 g, 0.9 mmol) in THFat 0° C. was added TBAF (1M in THF; 0.28 ml, 1.07 mmol, 1.2 eq.) and themixture was stirred for 0.5 h. The mixture was filtered over a pad ofsilica and distilled to give the product in 89% yield (0.31 g). ¹H NMR(300 MHz, DMSO-d₆): δ 10.3 (br s, 1H), 8.79 (s, 1H), 8.1 (s, 1H), 7.96(s, 1H), 7.88 (s, 1H), 7.82-7.73 (m, 2H), 7.54-7.45 (m, 3H), 7.34-7.27(m, 1H), 4.2 (s, 1H), 2.16 (s, 3H).

f)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

A mixture of the compound of Example 17(e) (115 mg, 0.297 mmol), sodiumazide (19 mg, 0.297 mmol, 1.0 eq.), methyl iodide (42 mg, 0.297 mmol,1.0 eq.), sodium ascorbate (59 mg, 0.297 mmol, 1.0 eq.) and coppersulfate pentahydrate (37 mg, 0.149 mmol, 0.5 eq.) in DMSO, THF and water(1:1:1, 3 ml) was stirred for 12 h at RT. The mixture was quenched withwater and the precipitate formed was filtered and dried. The crudeproduct was purified by preparative HPLC to give the product in 15%yield (20 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.7 (s, 1H),8.6 (s, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.7-7.95 (m, 4H), 7.4-7.55 (m,2H), 7.2-7.3 (m, 1H), 4.1 (s, 3H), 2.1 (s, 3H); LC-MS (ESI): Calculatedmass: 444.44; Observed mass: 445.1 [M+H]⁺ (rt: 1.039 min).

Example 18N-(2′,4′-difluoro-5-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide a)2′,4′-difluoro-5-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-amine

To a solution of the compound of Example 17 (300 mg, 0.675 mmol) inethanol (10 ml) was added aqueous solution of NaOH (338 mg, 8.44 mmol,12.5 eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 44% yield (0.12 g). LC-MS (ESI): Calculatedmass: 402.4; Observed mass: 403.4 [M+H]⁺ (rt: 1.03 min).

b)N-(2′,4′-difluoro-5-(5-(2-methyl-2H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 18(a) (90 mg, 0.224 mmol) inDCM was added pyridine (35 mg, 0.447 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (26 mg, 0.224 mmol, 1.0 eq.). The reaction wasmonitored by LCMS. After completion of the reaction the solvent wasremoved and the crude product was purified by preparative HPLC to givethe product in 13% yield (14 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.31 (s,1H), 8.84 (br s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.8-7.74(m, 2H), 7.59 (d, 2H), 7.49-7.43 (m, 2H), 7.31-7.26 (m, 1H), 4.11 (s,3H), 3.18 (s, 3H); LC-MS (ESI): Calculated mass: 480.49; Observed mass:481.1 [M+H]⁺ (rt: 1.357 min).

Example 19N-(2′,4′-difluoro-5-(5-(2-methyl-2H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)benzenesulfonamide

The compound was prepared from the compound of Example 17 using theprocedures of Example 18. ¹H NMR (300 MHz, DMSO-d₆): δ 10.9 (s, 1H),8.73 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.9-7.87 (m, 3H), 7.71-7.62(m, 4H), 7.55 (s, 1H), 7.47-7.39 (m, 4H), 7.28-7.24 (m, 1H), 4.12 (s,3H); LC-MS (ESI): Calculated mass: 542.56; Observed mass: 543.2 [M+H]⁺(rt: 1.52 min).

Example 20N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

A mixture of the compound of Example 17(e) (115 mg, 0.297 mmol),2-azido-N,N-dimethylethanamine (34 mg, 0.297 mmol, 1.0 eq.), sodiumascorbate (59 mg, 0.297 mmol, 1.0 eq.) and copper sulfate pentahydrate(37 mg, 0.149 mmol, 0.5 eq.) in DMSO, THF and water (1:1:1, 3 ml) wasstirred for 12 h at RT. The mixture was quenched with water and theprecipitate formed was filtered and dried. The crude product waspurified by preparative HPLC to give the product in 27% yield (40 mg).¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s, 1H), 8.71 (s, 2H), 8.25 (s, 1H),8.1 (s, 1H), 7.9 (d, 1H), 7.81-7.72 (m, 3H), 7.52 (s, 1H), 7.48-7.42 (m,1H), 7.3-7.25 (m, 1H), 4.82 (br s, 2H), 3.59 (br s, 2H), 2.78 (br s,6H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 501.53; Observed mass:502.2 [M+H]⁺ (rt: 0.259 min).

Example 21N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo-[d]imidazol-1-yl)biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 17(e) using theprocedures of Example 20. ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H),8.79 (s, 1H), 8.72 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.94-7.92 (m,1H), 7.82-7.72 (m, 3H), 7.54 (s, 1H), 7.48-7.42 (m, 1H), 7.3-7.25 (m,1H), 4.89 (t, 2H), 4.09 (m, 4H), 3.76 (m, 2H), 2.54-2.46 (m, 4H), 2.1(s, 3H); LC-MS (ESI): Calculated mass: 543.57; Observed mass: 544.2[M+H]⁺ (rt: 0.277 min).

Example 22N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-acetamidea)N-(2′,4′-difluoro-5-(4-formyl-2-nitrophenylamino)biphenyl-3-yl)acetamide

A solution of the compound of Example 1(e) (4.3 g, 16.4 mmol),4-fluoro-3-nitrobenzaldehyde of the Intermediate Example 4 (2.46 g, 16.4mmol, 1.0 eq.) and potassium fluoride (0.95 g, 16.4 mmol, 1.0 eq.) inDMF was heated at 130° C. for 5 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and thecrude residue was purified by column chromatography (60-120 silica gel,50% ethyl acetate in hexane) to yield the product in 45% yield (3.0 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.22 (s, 1H), 9.85 (s, 1H), 8.7 (s, 1H),7.93-7.9 (m, 1H), 7.73-7.58 (m, 3H), 7.43-7.2 (m, 5H), 2.07 (s, 3H).

b)N-(2′,4′-difluoro-5-(2-nitro-4-(oxazol-5-yl)phenylamino)biphenyl-3-yl)-acetamide

To a solution of the compound of Example 22(a) (2.0 g, 4.86 mmol) inmethanol was added potassium carbonate (0.74 g, 5.35 mmol, 1.1 eq.) andthe mixture was stirred for 10 min at RT. Toluenesulfonylmethylisocyanide (1.044 g, 5.35 mmol, 1.1 eq.) was added and the mixture wasrefluxed for 4 h. The methanol was distilled off and water was added tothe crude. The mixture was extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by column chromatography(60-120 silica gel, 40% ethyl acetate in hexane) to give the product in64% yield (1.4 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1H), 9.59 (s,1H), 8.45 (s, 1H), 8.4 (d, 1H), 7.91-7.87 (m, 1H), 7.71 (s, 2H),7.61-7.56 (m, 2H), 7.44-7.37 (m, 2H), 7.23-7.17 (m, 2H), 2.07 (s, 3H).

c)N-(5-(2-amino-4-(oxazol-5-yl)phenylamino)-2′,4′-difluorobiphenyl-3-yl)-acetamide

To a solution of the compound of Example 22(b) (1 g, 2.22 mmol) inmethanol (35 ml) and ethyl acetate (15 ml) was added 10% Pd/C (200 mg,0.2 eq.) and the reaction vessel was purged with nitrogen gas for 5 min.The mixture was then hydrogenated with H₂ balloon for 12 h. The mixturewas filtered through a pad of celite and the filtrate was concentratedto afford the compound in 86% yield (0.8 g).

d)N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

A mixture of the compound of Example 22(c) (1.5 g, 3.57 mmol) and formicacid (6 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 52%yield (0.8 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 8.74 (s, 1H),8.45 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.82-7.73 (m, 5H), 7.52 (s,1H), 7.5-7.2 (m, 1H), 7.27-7.23 (m, 1H), 2.11 (s, 3H); LC-MS (ESI):Calculated mass: 430.41; Observed mass: 431.2 [M+H]⁺ (rt: 1.42 min).

Example 23N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-methanesulfonamidea)2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-amine

To a solution of the compound of Example 22 (800 mg, 1.86 mmol) inethanol (10 ml) was added aqueous solution of NaOH (640 mg, 16 mmol, 8.6eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 69% yield (0.5 g). LC-MS (ESI): Calculatedmass: 388.37; Observed mass: 389.1 [M+H]⁺ (rt: 1.517 min).

b)N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 23(a) (100 mg, 0.258 mmol) inDCM was added pyridine (40 mg, 0.515 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (35 mg, 0.309 mmol, 1.2 eq.). The reaction wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the crude residue was purified bypreparative HPLC to give the product in 10% yield (12 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.78 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H),7.8-7.76 (m, 4H), 7.6-7.56 (m, 2H), 7.46 (m, 2H), 7.34-7.27 (m, 1H),3.18 (s, 3H); LC-MS (ESI): Calculated mass: 466.46; Observed mass: 467[M+H]⁺ (rt: 1.553 min).

Example 24N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-ethanesulfonamide

The compound was prepared from the compound of Example 22 using theprocedures of Example 23. ¹H NMR (300 MHz, DMSO-d₆): δ 10.33 (s, 1H),8.78 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.8-7.73 (m, 4H), 7.58-7.55(m, 2H), 7.48-7.43 (m, 2H), 7.29-7.25 (m, 1H), 3.29 (quartet, 2H), 1.25(t, 3H); LC-MS (ESI): Calculated mass: 480.49; Observed mass: 481.1[M+H]⁺ (rt: 1.517 min).

Example 25N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-propane-2-sulfonamide

The compound was prepared from the compound of Example 22 using theprocedures of Example 23. ¹H NMR (300 MHz, DMSO-d₆): δ 10.31 (s, 1H),8.8 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.78 (d, 4H), 7.58 (m, 2H),7.5-7.43 (m, 2H), 7.3-7.25 (m, 1H), 3.49-3.47 (m, 1H), 1.3 (d, 6H);LC-MS (ESI): Calculated mass: 495.41; Observed mass: 496.1 [M+H]⁺ (rt:1.66 min).

Example 26N-(2′,4′-difluoro-5-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-benzenesulfonamide

The compound was prepared from the compound of Example 22 using theprocedures of Example 23. ¹H NMR (300 MHz, DMSO-d₆): δ 10.9 (s, 1H),8.77 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.88 (d, 2H), 7.78-7.74 (m,2H), 7.72-7.61 (m, 4H), 7.54 (s, 1H), 7.49-7.45 (m, 1H), 7.43-7.39 (m,3H), 7.27-7.22 (m, 1H); LC-MS (ESI): Calculated mass: 528.53; Observedmass: 529.1 [M+H]⁺ (rt: 1.641 min).

Example 27N-(5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ 12.15 (br s, 1H),10.24 (s, 1H), 8.67 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.78-7.73 (m,2H), 7.65 (s, 1H), 7.53 (s, 1H), 7.48-7.43 (m, 1H), 7.3-7.25 (m, 2H),2.23 (s, 6H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 457.47;Observed mass: 458 [M+H]⁺ (rt: 0.75 min).

Example 28N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 1(h) (5 g, 11.31 mmol) in DMF(20 ml) were added pyrazole (5 g, 73.49 mmol, 6.5 eq.), copper(I) oxide(4.86 g, 33.92 mmol, 3.0 eq.) and cesium carbonate (14.73 g, 45.22 mmol,4.0 eq.) and the mixture was heated at 90° C. for 48 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offand the crude residue was purified by column chromatography (neutralalumina, 1% methanol in DCM) to give the product in 49% yield (2.4 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 8.8 (s, 1H), 8.6 (d, 1H),8.25 (s, 1H), 8.1 (s, 1H), 7.9-8.0 (m, 1H), 7.7-7.9 (m, 4H), 7.4-7.6 (m,2H), 7.2-7.3 (m, 1H), 6.6 (m, 1H), 2.1 (s, 3H); LC-MS (ESI): Calculatedmass: 429.42; Observed mass: 430.4 [M+H]⁺ (rt: 1.46 min).

Example 29N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamidea)5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-amine

To a solution of the compound of Example 28 (2.4 g, 5.59 mmol) inethanol (40 ml) was added aqueous solution of NaOH (2.4 g, 60 mmol, 10.7eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 69% yield (1.5 g).

b)N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 29(a) (250 mg, 0.645 mmol) inDCM was added pyridine (102 mg, 1.29 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (100 mg, 0.877 mmol, 1.4 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 33% yield (100 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.31 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 8.25 (d, 2H),7.95-7.92 (m, 1H), 7.84-7.77 (m, 3H), 7.62 (s, 1H), 7.58 (s, 1H),7.51-7.44 (m, 2H), 7.33-7.27 (m, 1H), 3.19 (s, 3H); LC-MS (ESI):Calculated mass: 465.48; Observed mass: 466.1 [M+H]⁺ (rt: 1.606 min).

Example 30N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 28 using theprocedures of Example 29. ¹H NMR (300 MHz, DMSO-d₆): δ 10.3-10.4 (Br s,1H), 8.75 (s, 1H), 8.6 (d, 1H), 8.25 (d, 1H), 7.9-7.95 (dd, 1H), 7.7-7.8(m, 3H), 7.55 (m, 2H), 7.4-7.5 (m, 2H), 7.3 (m, 1H), 6.55 (m, 1H), 4.1(q, 2H), 1.2-1.3 (t, 3H); LC-MS (ESI): Calculated mass: 479.5; Observedmass: 480.1 [M+H]⁺ (rt: 1.641 min).

Example 31N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 28 using theprocedures of Example 29. ¹H NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H),8.78 (s, 1H), 8.61 (d, 1H), 8.25 (d, 1H), 7.94 (dd, 1H), 7.78-7.75 (m,3H), 7.61-7.57 (m, 2H), 7.5-7.48 (m, 1H), 7.46-7.43 (m, 1H), 7.29-7.25(m, 1H), 6.6 (s, 1H), 3.5-3.46 (m, 1H), 1.31 (d, 6H); LC-MS (ESI):Calculated mass: 493.53; Observed mass: 494.1 [M+H]⁺ (rt: 1.61 min).

Example 32N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 28 using theprocedures of Example 29 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 10.34 (s, 1H), 9.0 (s, 1H), 8.64 (d, 1H), 8.27 (d, 1H),7.99 (dd, 1H), 7.85-7.76 (m, 3H), 7.65-7.62 (m, 2H), 7.54-7.45 (m, 2H),7.33-7.27 (m, 1H), 6.59-6.57 (m, 1H), 2.95-2.93 (m, 1H), 1.04-1.02 (m,4H); LC-MS (ESI): Calculated mass: 491.51; Observed mass: 492.1 [M+H]⁺(rt: 1.659 min).

Example 331-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 29(a) (250 mg, 0.645 mmol) inn-butanol was added TEA (200 mg, 1.98 mmol, 3.05 eq.) followed by2-(isocyanatomethyl) furan (160 mg, 1.3 mmol, 2.0 eq.). The mixture wasstirred for 1 h and then quenched and extracted as in Example 1(d). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 18% yield (60 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 9.07 (s, 1H), 8.84 (s, 1H), 8.61 (d, 1H), 8.24 (d, 1H),7.96-7.93 (m, 2H), 7.84-7.71 (m, 3H), 7.64-7.6 (m, 2H), 7.46-7.41 (m,2H), 7.27-7.23 (m, 1H), 6.82 (t, 1H), 6.58-6.56 (m, 1H), 6.41-6.4 (m,1H), 6.28-6.27 (m, 1H), 4.32 (d, 2H); LC-MS (ESI): Calculated mass:510.49; Observed mass: 511.1 [M+H]⁺ (rt: 1.59 min).

Example 34N-(5-(5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 28. ¹H NMR (300 MHz, DMSO-d₆): δ; 10.44 (s, 1H),8.86 (s, 1H), 8.29 (s, 2H), 8.14 (s, 1H), 7.92 (d, 2H), 7.79-7.71 (m,4H), 7.55 (s, 1H), 7.47-7.43 (m, 1H), 7.29-7.26 (m, 1H), 2.1 (s, 3H);LC-MS (ESI): Calculated mass: 429.42; Observed mass: 430.2 [M+H]⁺ (rt:0.21 min).

Example 35N-(2′,4′-difluoro-5-(4,5,6,7-tetrahydro-1′H-1,5′-bibenzo[d]imidazol-1′-yl)biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 28. ¹H NMR (300 MHz, CD₃OD): δ 8.66 (s, 1H), 8.15(t, 1H), 7.86-7.75 (m, 4H), 7.69-7.62 (m, 1H), 7.55 (d, 1H), 7.43 (dd,1H), 7.18-7.1 (m, 2H), 2.67-2.57 (m, 4H), 2.2 (s, 3H), 1.91-1.85 (m,4H); LC-MS (ESI): Calculated mass: 483.51; Observed mass: 484.2 [M+H]⁺(rt: 0.632 min).

Example 36N-(5-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

A solution of the compound of Example 17(c) (60 mg, 0.123 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(35 mg, 0.135 mmol, 1.1 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (20 mg, 0.025 mmol, 0.2 eq.) and aqueoussodium carbonate (39 mg, 0.369 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 25% yield (15mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.63 (s, 1H), 8.30 (s,1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.78-7.76(m, 2H), 7.63-7.61 (m, 1H), 7.51 (s, 1H), 7.45-7.40 (m, 1H); 7.27 (dt,1H), 4.73-4.69 (m, 1H), 2.12-2.01 (m, 5H), 2.01-1.96 (m, 2H), 1.85-1.81(m, 2H), 1.69-1.66 (m, 2H); LC-MS (ESI): Calculated mass: 497.54;Observed mass: 498.5 [M+H]⁺ (rt: 1.59 min).

Example 37N-(2′,4′-difluoro-5-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)acetamidea) tert-butyl4-(4-(1-(5-acetamido-2′,4′-difluorobiphenyl-3-yl)-1H-benzo[d]-imidazol-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of the compound of Example 17(c) (150 mg, 0.306 mmol) in1,2-dimethoxyethane (5 ml) was degassed by N₂ bubbling for 5 min.tert-Butyl4-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateof the Intermediate Example 5 (173 mg, 0.460 mmol, 1.5 eq.) was addedand the mixture was degassed for another 5 min. Pd(PPh₃)₄ (50 mg, 0.0613mmol, 0.2 eq.) and aqueous sodium carbonate (97 mg, 0.92 mmol, 3.0 eq.)were added and the procedure of Example 1(d) was followed. The cruderesidue of the product was obtained in 64% yield (120 mg).

b)N-(2′,4′-difluoro-5-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)acetamide

To a solution of the compound of Example 37(a) (120 mg, 0.2 mmol) in1,4-dioxane (8 ml) at 0° C. was added HCl in dioxane and stirred at RTfor 30 min. The solvent was distilled off and the residue was purifiedby preparative HPLC to give the product in 24% yield (25 mg). ¹H NMR(300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.83 (br s, 1H), 8.70-8.68 (m, 1H),8.45-8.43 (m, 1H) 8.34 (s, 1H), 8.14-8.13 (m, 1H), 8.06 (s, 2H), 7.78(m, 1H), 7.76-7.72 (m, 2H), 7.68 (dd, 1H), 7.53 (s, 1H), 7.43-7.40 (m,1H), 7.27 (dt, 1H), 4.55-4.45 (m, 1H), 3.17-3.08 (m, 4H), 2.28-2.17 (m,4H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 512.55; Observed mass:513.2 [M+H]⁺ (rt: 0.22 min).

Example 381-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)-3-cyclopentylurea

To a solution of the compound of Example 29(a) (200 mg, 0.52 mmol) inn-butanol (10 ml) was added triethylamine (157 mg, 1.56 mmol, 3 eq.)followed by iso-cyanatocyclopentane (115 mg, 1.3 mmol, 1.04 eq.). Themixture was stirred for 1 h and then quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby preparative HPLC to give the product in 15% yield (39 mg). ¹H NMR(300 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.72 (s, 1H), 8.60 (d, 1H), 8.23 (d,1H), 7.90 (dd, 2H), 7.82-7.70 (m, 3H), 7.60 (d, 1H), 7.45 (dt, 1H), 7.34(br s, 1H), 7.25 (dt, 1H), 6.57-6.56 (m, 1H), 6.46 (d, 1H), 4.0-3.93 (m,1H), 1.87-1.82 (m, 2H), 1.65-1.54 (m, 4H), 1.43-1.39 (m, 2H); LC-MS(ESI): Calculated mass: 498.53; Observed mass: 499.3 [M+H]⁺ (rt: 1.66min).

Example 39N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamidea)5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-amine

To a solution of the compound of Example 20 (450 mg, 0.9 mmol) inethanol (10 ml) was added aqueous solution of NaOH (450 mg, 11.25 mmol,12.5 eq.) and the mixture was heated at 85° C. for 2 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 77% yield (0.32 g).

b)N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 39(a) (80 mg, 0.174 mmol) inDCM (10 ml) was added pyridine (28 mg, 0.35 mmol, 2 eq.) followed bymethanesulfonyl chloride (22 mg, 0.19 mmol, 1.1 eq.). The mixture wasstirred for 2 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 11% yield (10 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.32 (s, 1H), 8.79 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H),7.92 (dd, 1H), 7.82-7.77 (m, 2H), 7.60 (d, 2H), 7.49-7.44 (m, 2H),7.30-7.27 (m, 1H), 4.88 (t, 2H), 3.73 (m, 2H), 3.19 (s, 3H), 2.89 (s,6H); LC-MS (ESI): Calculated mass: 537.58; Observed mass: 538.2 [M+H]⁺(rt: 0.243 min).

Example 40N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 20 using theprocedures of Example 39. ¹H NMR (300 MHz, DMSO-d₆): δ 10.37 (s, 1H),8.85 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.83 (d, 1H), 7.82-7.76 (m,2H), 7.59 (s, 2H), 7.48-7.47 (m, 2H), 7.29 (dt, 1H), 4.89-4.86 (m, 2H),3.73 (m, 2H), 3.30 (quartet, 2H), 2.90 (s, 6H), 1.26 (t, 3H); LC-MS(ESI): Calculated mass: 551.61; Observed mass: 552.2 [M+H]⁺ (rt: 0.282min).

Example 41N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 20 using theprocedures of Example 39. ¹H NMR (300 MHz, DMSO-d₆): δ 10.32 (s, 1H),8.79 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.93 (d, 1H), 7.80-7.75 (m,2H), 7.59 (d, 2H), 7.50-7.47 (m, 2H), 7.29 (dt, 1H), 4.88 (t, 2H), 3.74(m, 2H), 3.50-3.46 (m, 1H), 2.89 (s, 6H), 1.31 (d, 6H); LC-MS (ESI):Calculated mass: 565.64; Observed mass: 566.2 [M+H]⁺ (rt: 0.402 min).

Example 42N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 20 using theprocedures of Example 39 and cyclopropane sulfonyl chloride. ¹H NMR (400MHz, CD₃OD): δ 8.93 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.80 (d, 1H),7.82 (d, 1H), 7.68-7.58 (m, 4H), 7.17-7.10 (m, 2H), 4.95 (t, 2H), 3.85(t, 2H), 3.02 (s, 6H), 2.78-2.71 (m, 1H), 1.16-1.09 (m, 2H), 1.05-1.01(m, 2H); LC-MS (ESI): Calculated mass: 563.62; Observed mass: 564.2[M+H]⁺ (rt: 0.412 min).

Example 43N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)benzenesulfonamide

The compound was prepared from the compound of Example 20 using theprocedures of Example 39. ¹H NMR (300 MHz, DMSO-d₆): δ 10.92 (s, 1H),8.73 (d, 2H), 8.25 (s, 1H), 7.90-7.88 (m, 3H), 7.70-7.62 (m, 4H),7.55-7.38 (m, 5H), 7.26-7.20 (m, 1H), 4.90-4.87 (m, 2H), 3.73 (t, 2H),2.89 (s, 6H); LC-MS (ESI): Calculated mass: 599.65; Observed mass: 600.2[M+H]⁺ (rt: 0.75 min).

Example 44N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

A mixture of the compound of Example 17(e), 4-azido-2-methylbutan-2-olof Intermediate Example 6 (0.16 g, 1.25 mmol, 1.0 eq.), sodium ascorbate(0.25 g, 1.25 mmol, 1.0 eq.) and copper sulfate pentahydrate (0.155 g,0.62 mmol, 0.5 eq.) in CH₂Cl₂ (5 ml), DMSO (2 ml) and water (2 ml) wasstirred for 12 h at RT. The mixture was quenched with water and theprecipitate formed was filtered and dried. The crude product waspurified by preparative HPLC to give the product in 62% yield (0.4 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H),8.25 (s, 1H), 8.09 (s, 1H), 7.93 (d, 1H), 7.84-7.81 (m, 3H), 7.55 (s,1H), 7.50-7.43 (m, 1H), 7.30-7.25 (m, 1H), 4.51-4.56 (m, 2H), 2.13 (s,3H), 2.05-1.99 (t, 2H), 1.18 (s, 6H); LC-MS (ESI): Calculated mass:516.54; Observed mass: 517.2 [M+H]⁺ (rt: 1.226 min).

Example 45N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamidea)4-(4-(1-(5-amino-2′,4′-difluorobiphenyl-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-methylbutan-2-ol

To a solution of the compound of Example 44 (400 mg, 0.77 mmol) inethanol (20 ml) was added aqueous solution of NaOH (385 mg, 9.63 mmol,12.5 eq.) and the mixture was heated at 90° C. for 3 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto give the product in 38% yield (140 mg).

b)N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 45(a) (70 mg, 0.15 mmol) in DCM(10 ml) was added pyridine (24 mg, 0.3 mmol, 2 eq.) followed bymethanesulfonyl chloride (19 mg, 0.165 mmol, 1.1 eq.). The mixture wasstirred for 2 h, and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 1.2% yield (1 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.30 (s, 1H), 8.83 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H),7.92 (d, 1H), 7.82-7.80 (m, 2H), 7.60 (d, 2H), 7.47 (s, 2H), 7.29-7.21(m, 1H), 4.49 (m, 2H), 3.19 (s, 3H), 2.02 (m, 2H), 1.18 (s, 6H); LC-MS(ESI): Calculated mass: 552.60; Observed mass: 553.1 [M+H]⁺ (rt: 1.352min).

Example 46N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 44 using theprocedures of Example 45. ¹H NMR (300 MHz, DMSO-d₆): δ 10.34 (s, 1H),8.87 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H), 7.93 (dd, 1H), 7.84-7.80 (m,2H), 7.59 (s, 2H), 7.49-7.44 (m, 2H), 7.29 (dt, 1H), 4.51-4.47 (m, 2H),3.30 (quartet, 2H), 2.04-2.00 (m, 2H), 1.26 (t, 3H), 1.16 (s, 6H); LC-MS(ESI): Calculated mass: 566.62; Observed mass: 567.2 [M+H]⁺ (rt: 1.42min).

Example 47N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 44 using theprocedures of Example 45 and cyclopropane sulfonyl chloride. ¹H NMR (400MHz, CD₃OD): δ 9.09 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.0 (d, 1H),7.83 (d, 1H), 7.69-7.60 (m, 4H), 7.17-7.10 (m, 2H), 4.62-4.58 (m, 2H),2.78-2.69 (m, 1H), 2.17-2.13 (m, 2H), 1.29-1.15 (m, 8H), 1.10-1.02 (m,2H); LC-MS (ESI): Calculated mass: 578.63; Observed mass: 579.2 [M+H]⁺(rt: 1.449 min).

Example 48N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamidea)2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-amine

To a solution of the compound of Example 21 (1 g, 1.9 mmol) in ethanol(15 ml) was added aqueous solution of NaOH (0.95 g, 23.8 mmol, 12.5 eq.)and the mixture was heated at 90° C. for 4 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was distilled off toafford the product in 63% yield (600 mg).

b)N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 48(a) (80 mg, 0.159 mmol) inDCM (10 ml) was added pyridine (25 mg, 0.318 mmol, 2 eq.) followed bymethanesulfonyl chloride (21 mg, 0.191 mmol, 1.2 eq.). The mixture wasstirred for 2 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 13% yield (12 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.32 (s, 1H), 8.80 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H),7.94-7.92 (d, 1H), 7.82-7.72 (m, 2H), 7.60 (d, 2H), 7.46-7.40 (m, 2H),7.27 (dt, 1H), 4.89 (m, 2H), 3.96-3.94 (m, 6H), 3.77 (m, 4H), 3.19 (s,3H); LC-MS (ESI): Calculated mass: 579.62; Observed mass: 580.2 [M+H]⁺(rt: 0.29 min).

Example 49N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 21 using theprocedures of Example 48. ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H),8.83 (s, 1H), 8.80 (s, 1H), 8.32 (s, 1H), 7.97 (d, 1H), 7.85-7.80 (m,2H), 7.63 (s, 2H), 7.52-7.50 (m, 2H), 7.33 (d, 1H), 4.93 (m, 2H), 4.0(m, 6H), 3.70 (m, 4H), 3.34 (quartet, 2H), 1.30 (t, 3H); LC-MS (ESI):Calculated mass: 593.65; Observed mass: 594.2 [M+H]⁺ (rt: 0.36 min).

Example 50N-(2′,4′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 21 using theprocedures of Example 48 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 10.9 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H),7.9-7.87 (m, 3H), 7.71-7.62 (m, 4H), 7.55 (s, 1H), 7.47-7.39 (m, 4H),7.28-7.24 (m, 1H), 4.12 (s, 3H); LC-MS (ESI): Calculated mass: 605.6;Observed mass: 606.2 [M+H]⁺ (rt: 0.367 min).

Example 51N-(5-(5-(1-cyclopentyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

A solution of the compound of Example 17(e) (100 mg, 0.258 mmol) in dryDMF (10 ml) in a sealed tube was purged with N₂ for 20 min, followed bythe addition of azidocyclopentane of Intermediate Example 7 (34 mg, 0.3mmol, 1.2 eq.) and copper iodide (5 mg, 0.0258 mmol, 0.1 eq.) andstirred at 90° C. for 12 h. The solvent was distilled off and theresidue was purified by preparative HPLC to give the product in 14%yield (18 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.55 (s, 1H), 8.43 (s, 1H),8.36 (s, 1H), 8.23 (br s, 1H), 8.10 (s, 1H), 7.92-7.88 (m, 1H), 7.74 (d,2H), 7.68-7.61 (m, 1H), 7.52 (s, 1H), 7.15-7.09 (m, 1H), 5.09-5.03 (m,1H), 2.35-2.30 (m, 2H), 2.19-2.12 (m, 5H), 1.96-1.90 (m, 4H); LC-MS(ESI): Calculated mass: 498.53; Observed mass: 499.2 [M+H]⁺ (rt: 1.55min).

Example 52N-(5-(5-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 17(e) using thecompound of Intermediate Example 8 and the procedure of Example 51. ¹HNMR (300 MHz, DMSO-d₆): δ 10.34 (s, 1H), 8.13 (s, 1H), 8.61 (s, 1H),8.24 (s, 1H), 8.07 (s, 1H), 7.92-7.90 (d, 1H), 7.82-7.71 (m, 3H), 7.52(s, 1H), 7.42 (m, 1H), 7.24-7.20 (m, 1H), 4.42 (d, 2H), 2.10 (s, 3H),2.05 (m, 3H), 1.90-1.83 (m, 4H); LC-MS (ESI): Calculated mass: 498.53;Observed mass: 499.2 [M+H]⁺ (rt: 1.55 min).

Example 53N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamidea) N-(4′-fluoro-5-nitrobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 1(c) (10.0 g,38.6 mmol) using the procedure of Example 1(d) and 4-fluorophenylboronicacid (6.48 g, 46.3 mmol, 1.2 eq.) to give the product in 86% yield (9.1g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.53 (s, 1H), 8.57 (t, 1H), 8.17 (s,1H), 8.09 (t, 1H), 7.86-7.74 (m, 2H), 7.41 (t, 2H), 7.15 (t, 1H), 2.13(s, 3H); LC-MS (ESI): Calculated mass: 274.25; Observed mass: 274.8[M+H]⁺ (rt: 1.52 min).

b) N-(5-amino-4′-fluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(a) (11.0 g,40.1 mmol) using the procedure of Example 1(e) to afford the compound in92% yield (9.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 9.73 (s, 1H), 8.11 (s,1H), 7.53-7.48 (m, 2H), 7.26 (t, 1H), 6.94-6.92 (m, 2H), 6.47 (s, 1H),5.22 (s, 2H), 2.02 (s, 3H); LC-MS (ESI): Calculated mass: 244.26;Observed mass: 245.1 [M+H]⁺ (rt: 0.312 min).

c) N-(5-(4-bromo-2-nitrophenylamino)-4′-fluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(b) (9.0 g,36.85 mmol) using the procedure of Example 1(f). The reaction wasquenched with water. The precipitate formed was filtered, washed withcold water and hexane and dried under high vacuum to give the product asorange solid in 92% yield (15.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.14(s, 1H), 9.45 (s, 1H), 8.25 (d, 1H), 7.69-7.62 (m, 5H), 7.35-7.24 (m,4H), 2.07 (s, 3H); LC-MS (ESI): Calculated mass: 444.25; Observed mass:446.1 [M+H]⁺ (rt: 1.84 min).

d) N-(5-(2-amino-4-bromophenylamino)-4′-fluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(c) (15 g,33.77 mmol) using the procedure of Example 1(g) to afford the product in93% yield (13.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 9.84 (1H, s), 7.53-7.49(m, 3H), 7.31-7.25 (m, 4H), 6.98-6.91 (m, 2H), 6.88-6.62 (m, 2H), 5.11(s, 2H), 2.01 (s, 3H); LC-MS (ESI): Calculated mass: 414.27; Observedmass: 416 [M+H]⁺ (rt: 1.73 min).

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(d) (13.0 g,31.38 mmol) using the procedure of Example 1(h) to afford the product in68% yield (9.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.38 (s, 1H), 8.77 (s,1H), 8.14 (s, 1H), 8.02-7.97 (m, 1H), 7.9 (s, 1H), 7.82-7.77 (m, 2H),7.7-7.67 (m, 1H), 7.63-7.62 (m, 1H), 7.54-7.5 (m, 1H), 7.36 (t, 2H),2.12 (s, 3H); LC-MS (ESI): Calculated mass: 424.27; Observed mass: 425.1[M+H]⁺ (rt: 1.925 min).

f)N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(e) (1.3 g,3.06 mmol) using the procedure of Example 1(i) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.765 g, 3.68 mmol, 1.2 eq.) to give the product in 46% yield (0.6 g).¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 9.0 (s, 1H), 8.25 (s, 1H),8.08 (s, 1H), 8.0 (d, 2H), 7.90 (s, 1H), 7.8 (m, 3H), 7.65 (m, 2H), 7.4(t, 2H), 3.9 (s, 3H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 425.46;Observed mass: 425.9 [M+H]⁺ (rt: 1.13 min).

Example 54N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamidea)4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-amine

To a solution of the compound of Example 53 (0.6 g, 1.41 mmol) inethanol (20 ml) was added aqueous solution of NaOH (451 mg, 11.3 mmol,8.0 eq.) and the mixture was heated at 85° C. for 4 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 44% yield (0.24 g). LC-MS (ESI): Calculatedmass: 383.42; Observed mass: 384.1 [M+H]⁺ (rt: 1.004 min).

b)N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 54(a) (50 mg, 0.125 mmol) inDCM was added pyridine (20 mg, 0.249 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (17 mg, 0.15 mmol, 1.2 eq.). The mixture wasstirred for 1 h quenched and extracted as in Example 2(b). The solventwas distilled off and the residue was purified by preparative HPLC togive the product in 33% yield (20 mg). ¹H NMR (300 MHz, DMSO-d₆): δ10.23 (br s, 1H), 8.71 (s, 1H), 7.97 (d, 2H), 7.85-7.8 (m, 2H), 7.69 (m,2H), 7.61-7.58 (m, 2H), 7.52 (d, 2H), 7.38 (t, 2H), 3.89 (s, 3H), 3.19(s, 3H); LC-MS (ESI): Calculated mass: 461.51; Observed mass: 461.9[M+H]⁺ (rt: 1.3 min).

Example 55N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 53 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.36 (br s, 1H),9.35 (br s, 1H), 8.28 (s, 1H), 8.02 (d, 2H), 7.85-7.79 (m, 2H), 7.76-7.7(m, 3H), 7.6-7.57 (m, 2H), 7.39 (t, 2H), 3.89 (s, 3H), 3.31 (quartet,2H), 1.27 (t, 3H); LC-MS (ESI): Calculated mass: 475.54; Observed mass:475.9 [M+H]⁺ (rt: 1.38 min).

Example 56N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 53 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.28 (br s, 1H),8.92 (br s, 1H), 8.24 (s, 1H), 7.99 (d, 2H), 7.83-7.78 (m, 2H),7.71-7.67 (m, 3H), 7.56 (d, 2H), 7.38 (t, 2H), 3.88 (s, 3H), 3.52-3.48(m, 1H), 1.31 (d, 6H); LC-MS (ESI): Calculated mass: 489.56; Observedmass: 490.2 [M+H]⁺ (rt: 1.46 min).

Example 57N-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 53 using theprocedures of Example 54 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.1 (br s, 1H), 8.26 (s, 1H), 8.01 (d,2H), 7.84-7.81 (m, 2H), 7.74-7.71 (m, 3H), 7.59 (s, 2H), 7.39 (t, 2H),3.89 (s, 3H), 2.91-2.89 (m, 1H), 1.03 (d, 4H); LC-MS (ESI): Calculatedmass: 487.55; Observed mass: 488.1 [M+H]⁺ (rt: 1.42 min).

Example 581-cyclopentyl-3-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)urea

To a solution of the compound of Example 54(a) (100 mg, 0.261 mmol) inn-butanol was added triethylamine (79 mg, 0.783 mmol, 3.0 eq.) followedby isocyanato-cyclopentane (58 mg, 0.522 mmol, 2.0 eq.). The mixture wasstirred for 1 h and then quenched and extracted as in Example 1(d). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 31% yield (40 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 8.84 (br s, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 7.99 (d, 2H),7.88 (s, 1H), 7.82-7.78 (m, 2H), 7.73 (d, 1H), 7.68-7.63 (m, 2H), 7.48(s, 1H), 7.36 (t, 2H), 6.4 (d, 1H), 4.1-3.8 (m, 1H), 3.88 (s, 3H),1.89-1.83 (m, 2H), 1.69-1.5 (m, 4H), 1.45-1.38 (m, 2H); LC-MS (ESI):Calculated mass: 494.56; Observed mass: 494.8 [M+H]⁺ (rt: 1.51 min).

Example 591-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-3-(1-methylpiperidin-4-yl)urea

To a solution of the compound of Example 54(a) (50 mg, 0.13 mmol) in DCMat 0° C. was added phosgene (20% in toluene) (0.1 ml, 0.195 mmol, 1.5eq.) and the mixture was stirred for 15 min at 0° C. and 30 min at RT.1-Methylpiperidin-4-amine (18 mg, 0.156 mmol, 1.2 eq.) was added and themixture was stirred for 16 h. The mixture was quenched by the additionof water and extracted with 8% methanol/DCM (3×50 ml). The combinedorganic layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and the residue was purified bypreparative HPLC to give the product in 44% yield (30 mg). ¹H NMR (300MHz, DMSO-d₆): δ 8.48 (s, 1H), 7.98 (s, 1H), 7.89-7.85 (m, 4H),7.72-7.55 (m, 6H), 7.39 (s, 1H), 7.2 (t, 2H), 3.94 (s, 3H), 3.89-3.84(m, 1H), 3.42-3.33 (m, 2H), 3.05-3.0 (m, 2H), 2.78 (s, 3H), 2.17-2.13(m, 2H), 1.85-1.81 (m, 2H); LC-MS (ESI): Calculated mass: 523.6;Observed mass: 524 [M+H]⁺ (rt: 0.2 min).

Example 601-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-3-(furan-2-ylmethyl)urea

The compound was prepared from the compound of Example 54(a) using theprocedures of Example 58. ¹H NMR (300 MHz, CD₃OD): δ 6 9.1 (s, 1H), 8.1(s, 1H), 8.02 (s, 2H), 7.93 (s, 1H), 7.85-7.81 (m, 2H), 7.74-7.67 (m,3H), 7.53 (d, 1H), 7.44 (d, 1H), 7.22 (t, 2H), 6.37-6.34 (m, 1H),6.3-6.29 (m, 1H), 4.42 (s, 2H), 3.95 (s, 3H); LC-MS (ESI): Calculatedmass: 506.53; Observed mass: 507.1 [M+H]⁺ (rt: 1.44 min).

Example 611-(4′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-3-((5-methylfuran-2-yl)methyl)urea

The compound was prepared from the compound of Example 54(a) using theprocedures of Example 58. ¹H NMR (300 MHz, CD₃OD): δ 9.51 (s, 1H), 8.1(s, 1H), 8.02 (s, 2H), 7.93 (s, 1H), 7.85-7.73 (m, 4H), 7.65 (m, 1H),7.53 (s, 1H), 7.22 (t, 2H), 6.2-6.14 (m, 1H), 5.9-5.81 (m, 1H), 4.38 (s,2H), 3.95 (s, 3H), 2.26 (s, 3H); LC-MS (ESI): Calculated mass: 520.56;Observed mass: 521.1 [M+H]⁺ (rt: 1.51 min).

Example 62N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 53(e) using theprocedures of Example 53. ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H),8.98 (s, 1H), 8.37 (s, 1H), 8.14-8.06 (m, 3H), 7.85-7.75 (m, 4H),7.68-7.66 (m, 2H), 7.38 (t, 2H), 4.57 (t, 2H), 3.65-3.63 (m, 2H), 2.85(d, 6H), 2.13 (s, 3H); LC-MS (ESI): Calculated mass: 482.55; Observedmass: 483.1 [M+H]⁺ (rt: 0.19 min).

Example 63N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 62 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.27 (s, 1H),8.87 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.84-7.8 (m,2H), 7.76-7.64 (m, 3H), 7.55-7.52 (m, 2H), 7.38 (t, 2H), 4.57 (t, 2H),3.65-3.62 (m, 2H), 3.19 (s, 3H), 2.86 (d, 6H); LC-MS (ESI): Calculatedmass: 518.61; Observed mass: 519 [M+H]⁺ (rt: 0.22 min).

Example 64N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 62 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.29 (s, 1H),8.77 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.83-7.78 (m,2H), 7.72-7.63 (m, 3H), 7.54-7.51 (m, 2H), 7.38 (t, 2H), 4.57 (t, 2H),0.65-3.62 (m, 2H), 3.3 (quartet, 2H), 2.86 (d, 6H), 1.27 (t, 3H); LC-MS(ESI): Calculated mass: 532.63; Observed mass: 533 [M+H]⁺ (rt: 0.25min).

Example 65N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 62 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.27 (s, 1H),8.82 (s 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.83-7.79 (m,2H), 7.71-7.65 (m, 3H), 7.56-7.53 (m, 2H), 7.38 (t, 2H), 4.57 (t, 2H),3.67-3.64 (m, 2H), 3.52-3.49 (m, 1H), 2.85 (d, 6H), 1.32 (d, 6H); LC-MS(ESI): Calculated mass: 546.66; Observed mass: 547.2 [M+H]⁺ (rt: 0.507min).

Example 66N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 62 using theprocedures of Example 54 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, DMSO-d₆): δ 10.26 (s, 1H), 8.84 (s, 1H), 8.36 (s, 1H), 8.14 (s,1H), 8.06 (s, 1H), 7.82-7.79 (m, 2H), 7.73-7.67 (m, 3H), 7.56 (d, 2H),7.39 (t, 2H), 4.57 (t, 2H), 3.65-3.62 (m, 2H), 2.9-2.87 (m, 1H), 2.86(d, 6H), 1.02 (d, 4H); LC-MS (ESI): Calculated mass: 544.64; Observedmass: 546.2 [M+H]⁺ (rt: 0.401 min).

Example 67N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)benzenesulfonamide

The compound was prepared from the compound of Example 62 using theprocedures of Example 54. ¹H NMR (300 MHz, DMSO-d₆): δ 10.9 (s, 1H),8.78 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.89 (d, 2H),7.72-7.68 (m, 3H), 7.66-7.61 (m, 4H), 7.41-7.33 (m, 5H), 4.57 (t, 2H),3.66-3.63 (m, 2H), 2.85 (d, 6H); LC-MS (ESI): Calculated mass: 580.68;Observed mass: 581.1 [M+H]⁺ (rt: 0.781 min).

Example 681-cyclopentyl-3-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)urea

The compound was prepared from the compound of Example 62 using theprocedures of Example 58. ¹H NMR (300 MHz, DMSO-d₆): δ 9.33 (br s, 1H),8.87 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H),7.39 (m, 1H), 7.82-7.75 (m, 3H), 7.68-7.6 (m, 2H), 7.48 (m, 1H), 7.36(t, 2H), 4.57 (t, 2H), 3.99-3.97 (m, 1H), 3.65-3.62 (m, 2H), 2.86 (d,6H), 1.89-1.82 (m, 2H), 1.7-1.53 (m, 4H), 1.45-1.37 (m, 2H); LC-MS(ESI): Calculated mass: 551.66; Observed mass: 552.2 [M+H]⁺ (rt: 0.61min).

Example 69N-(4′-fluoro-5-(5-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

The compound was prepared using the procedures of Example 53. ¹H NMR(300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 8.96 (s, 1H), 8.58 (d, 1H),8.15-8.07 (m, 3H), 7.91-7.89 (m, 1H), 7.85-7.79 (m, 3H), 7.74-7.67 (m,2H), 7.38 (t, 2H), 6.95 (d, 1H), 3.92 (s, 3H), 2.14 (s, 3H); LC-MS(ESI): Calculated mass: 452.48; Observed mass: 453.1 [M+H]⁺ (rt: 1.571min).

Example 70N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)-acetamide

To a solution of the compound of Example 53(e) (1.0 g, 2.36 mmol) in DMF(5 ml) were added pyrazole (1.0 mg, 14.87 mmol, 6.3 eq.), copper(I)oxide (1.0 g, 7.08 mmol, 3.0 eq.) and cesium carbonate (3.0 g, 9.204mmol, 3.9 eq.) and the mixture was heated at 90° C. for 48 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by preparative HPLC to givethe product in 62% yield (0.6 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s,1H), 8.8 (s, 1H), 8.6 (d, 1H), 8.24 (d, 1H), 8.02 (s, 1H), 7.93-7.9 (m,2H), 7.82-7.56 (m, 4H), 7.65 (d, 1H), 7.37 (t, 2H), 6.56 (t, 1H), 2.13(s, 3H); LC-MS (ESI): Calculated mass: 411.43; Observed mass: 412.3[M+H]⁺ (rt: 1.43 min).

Example 71N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)-methanesulfonamidea)5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-amine

To a solution of the compound of Example 70 (0.6 g, 1.46 mmol) inethanol (40 ml) was added aqueous solution of NaOH (1.0 g, 25 mmol, 17.1eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The combined organic layerwas washed with water, brine and dried over sodium sulphate. The solventwas distilled off to afford the product in 84% yield (0.45 g).

b)N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 71(a) (150 mg, 0.406 mmol) inDCM was added pyridine (0.5 ml, 6.21 mmol, 15.3 eq.) followed bymethanesulfonyl chloride (70 mg, 0.609 mmol, 1.5 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 17% yield (30 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.23 (s, 1H), 8.82 (s, 1H), 8.6 (d, 1H), 8.24 (d, 1H), 7.92(dd, 1H), 7.85-7.8 (m, 3H), 7.76-7.71 (m, 2H), 7.54-7.53 (m, 2H), 7.38(t, 2H), 6.56 (t, 1H), 3.19 (s, 3H); LC-MS (ESI): Calculated mass:447.48; Observed mass: 449.1 [M+H]⁺ (rt: 1.575 min).

Example 72N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluorobiphenyl-3-yl)-ethanesulfonamide

The compound was prepared from the compound of Example 70 using theprocedures of Example 71. ¹H NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H),8.81 (s, 1H), 8.6 (d, 1H), 8.24 (s, 1H), 7.93 (dd, 1H), 7.84-7.76 (m,4H), 7.7-7.69 (m, 1H), 7.55-7.53 (m, 2H), 7.4-7.36 (m, 2H), 6.57-6.56(m, 1H), 3.3 (quartet, 2H), 1.27 (t, 3H); LC-MS (ESI): Calculated mass:461.51; Observed mass: 462.1 [M+H]⁺ (rt: 1.563 min).

Example 73N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)acetamidea) N-[3-(5-Methyl-furan-2-yl)-5-nitro-phenyl]-acetamide

To a solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (5g, 19.23 mmol) in 1,2-dimethoxyethane (200 ml) were added4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (5.9 g,28.85 mmol), sodium carbonate (8.15 g, 76.92 mmol) and water (20 ml) andthe mixture was degassed by N₂ bubbling 15 min. Pd(dppf)Cl₂ (3.2 g,3.846 mmol) was added and the mixture was heated at 100° C. for 2 h. Themixture was brought to RT and quenched and extracted as in Example 1(d).The solvent was distilled off and the residue was purified by flashcolumn chromatography (40% ethyl acetate in hexanes) to afford theproduct in 80% yield (4.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.45 (s,1H), 8.4 (s, 1H), 8.2 (d, 2H), 7.1 (s, 1H), 6.2 (s, 1H), 2.4 (s, 3H),2.15 (s, 3H), Calculated mass: 260.25; Observed mass: 259.1 [M+H](rt:1.578 min).

b) N-[3-Amino-5-(5-methyl-furan-2-yl)-phenyl]-acetamide

To a solution of the compound of Example 73(a) (4.0 g, 15.384 mmol) inmethanol (50 ml) was added 10% palladium in carbon (500 mg) and themixture was stirred at RT under hydrogen atmosphere (balloon pressure)for 6 h. The mixture was filtered over a pad of celite and washed withmethanol. The solvent was evaporated to afford the compound in 95% yield(3.3 g). ¹H NMR (300 MHz, DMSO-d₆): δ 9.6 (s, 1H), 7.0 (d, 2H), 6.45 (d,2H), 6.2 (s, 1H), 5.2 (s, 2H), 2.4 (s, 3H), 2.15 (s, 3H), Calculatedmass: 230.26; Observed mass: 231.2 [M+H]⁺ (rt: 0.212 min).

c)N-[3-(4-Bromo-2-nitro-phenylamino)-5-(5-methyl-furan-2-yl)-phenyl]-acetamide

To a solution of the compound of Example 73(b) (5 g, 22.73 mmol) inanhydrous DMF (25 ml), 4-bromo-1-fluoro-2-nitrobenzene (7.09 g, 27.3mmol) and potassium fluoride (1.32 g, 22.73 mmol) were added. Themixture was stirred at 100° C. overnight. The mixture was brought to RTand DMF was removed under reduced pressure. The residue was purified byflash column chromatography (50% ethyl acetate in hexanes) to give thecompound in 65% yield (6 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.2 (s, 1H),9.6 (s, 1H), 8.2 (s, 1H), 7.7 (s, 2H), 7.5 (m, 1H), 7.30 (s, 1H), 7.2(s, 1H), 6.7 (d, 1H), 2.9 (s, 1H), 2.33 (s, 3H), 2.15 (s, 3H),Calculated mass: 430.25; Observed mass: 432 [M+H]⁺ (rt: 1.85 min).

d)N-[3-(2-Amino-4-bromo-phenylamino)-5-(5-methyl-furan-2-yl)-phenyl]-acetamide

To a solution of the compound of Example 73(c) (6.0 g, 13.945 mmol) inethanol (100 ml) were added iron powder (500 mg) and 50% aqueous calciumchloride solution (10 ml). The mixture was stirred at 80° C. for 2 h andfiltered through a celite pad. The celite pad was washed with ethylacetate (200 ml). The combined organic layer was washed with water,brine and dried over sodium sulphate. The solvent was distilled off andthe residue was purified by flash column chromatography (20% ethylacetate in hexanes) to get the compound in 98% yield (5.5 g). ¹H NMR(300 MHz, DMSO-d₆): δ 9.8 (s, 1H), 7.30 (d, 1H), 6.9 (m, 3H), 6.7 (m,2H), 6.5 (d, 1H), 5.2 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H), Calculatedmass: 400.27; Observed mass: 402 [M+H]⁺ (rt: 1.695 min).

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)-acetamide

Formic acid (10 ml) was added to the compound of Example 73(d) (5 g,12.49 mmol) at RT and then the mixture was heated at 100° C. for 2 h.Formic acid was removed and the residue was purified by flash columnchromatography (3% methanol in chloroform) to afford the compound in 58%yield (3.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.7 (s, 1H),8.0 (s, 1H), 7.9 (s, 2H), 7.6 (m, 2H), 7.5 (m, 1H), 7.0 (s, 1H), 6.3 (d,1H), 2.33 (s, 3H), 2.15 (s, 3H), Calculated mass: 410.26; Observed mass:410.2 [M+H]⁺ (rt: 1.616 min).

f)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)acetamide

To a solution of the compound of Example 73(e) (100 mg, 0.244 mmmol) in1,2-dimethoxyethane (10 ml),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.043 g, 0.341 mmol), sodium carbonate (0.0755 g, 0.731 mmol) and water(2.0 ml) were added and the mixture was degassed for 15 min by N₂bubbling. Pd(PPh₃)₄ (0.0563 g, 0.0487 mmol) was added and the mixturewas heated at 100° C. for 2 h. The mixture was brought to RT and thenquenched and extracted as in Example 1(d). The solvent was distilled offand the residue was purified by preparative HPLC to afford the compoundin 10% yield (10 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.2 (s, 1H), 8.6 (s,1H), 8.4 (s, 1H), 7.8-8.1 (s, 4H), 7.6-7.7 (m, 4H), 7.0 (s, 1H), 6.3 (s,1H), 3.9 (m, 1H), 2.4 (s, 3H), 2.15 (s, 4H), Calculated mass: 411.46;Observed mass: 412.1 [M+H]⁺ (rt: 0.809 min).

Example 74N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)ethanesulfonamidea)3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)aniline

A mixture of KOH (0.614 g, 10.94 mmol) and the compound of Example 73(3.0 g, 7.29 mmol) in ethanol (5 ml) and water (2 ml) was heated at 60°C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and waswashed with water (50 ml) and brine (25 ml). The organic phase was driedover sodium sulfate and concentrated under vacuum and the residue waspurified by column chromatography to afford the product in 92% yield(2.5 g).

b)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)ethanesulfonamide

To a solution of the compound of Example 74(a) (0.1 g, 0.27 mmol) inpyridine (1 ml) and DCM (2 ml) was added ethanesulfonyl chloride (0.1ml) and the mixture was stirred at RT for 12 h. The solvent was removedand the crude was purified by preparative HPLC to afford the product in24% yield (0.03 g). ¹H NMR (300 MHz, CD₃OD): δ 9.2 (s, 1H), 8.1 (s, 1H),8.0 (s, 1H), 7.95 (s, 1H), 7.6-7.7 (m, 4H), 7.5 (s, 1H), 6.8 (d, 1H),6.2 (s, 1H), 4.0 (s, 3H), 3.3 (m, 2H), 2.4 (s, 3H), 1.4 (t, 3H). LC-MS(ESI): Calculated mass: 461.54; Observed mass: 462.1 [M+H]⁺ (rt: 1.315min).

Example 75N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)propane-2-sulfonamide

The compound was prepared from the compound of Example 73 using theprocedures of Example 74. ¹H NMR (300 MHz, CD₃OD): δ; 8.5 (s, 1H), 8.0(s, 1H), 7.95 (s, 1H), 7.9 (s, 1H), 7.6-7.7 (m, 5H), 7.5 (s, 1H), 6.8(d, 1H), 6.2 (s, 1H), 4.0 (s, 3H), 3.5 (m, 1H), 2.4 (s, 3H), 1.5 (d,6H). LC-MS (ESI): Calculated mass: 475.56; Observed mass: 475.9 [M+H]⁺(rt: 1.415 min).

Example 76N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 73 using theprocedures of Example 74 and cyclopropane sulfonyl chloride. ¹H NMR (300MHz, CD₃OD): δ 8.5 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.9 (s, 1H),7.6-7.7 (m, 4H), 7.5 (s, 1H), 6.8 (d, 1H), 6.2 (s, 1H), 4.0 (s, 3H), 2.4(s, 3H), 1.0-1.5 (m, 4H). LC-MS (ESI): Calculated mass: 473.55; Observedmass: 474.0 [M+H]⁺ (rt: 1.382 min).

Example 77N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)benzenesulfonamide

The compound was prepared from the compound of Example 73 using theprocedures of Example 74. Yield 0.03 g, (25%), ¹H NMR (300 MHz, CD₃OD):δ; 8.55 (s, 1H), 8.05 (s, 1H), 7.9 (m, 4H), 7.6-7.7 (m, 5H), 7.5 (s,2H), 7.4 (d, 1H), 7.2 (t, 1H), 6.8 (d, 1H), 6.2 (s, 1H), 4.0 (s, 3H),2.4 (s, 3H). LC-MS (ESI): Calculated mass: 509.58; Observed mass: 509.9[M+H]⁺ (rt: 1.482 min).

Example 781-(furan-2-ylmethyl)-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)urea

To a solution of the compound of Example 74(a) (0.1 g, 0.271 mmol) inDCM (10 ml), at 0° C., were added phosgene (0.04 g, 0.406 mmol) andfurfuryl amine (0.029 g, 0.2977 mmol) sequentially. The mixture washeated at 60° C. for 2 h and the solvent was evaporated and the residuewas purified by preparative HPLC to give the compound in 15% yield (20mg). ¹H NMR (300 MHz, CD₃OD): δ 9.6 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H),7.95 (s, 2H), 7.6-7.7 (m, 5H), 7.7 (s, 1H), 7.6 (s, 1H), 6.4 (s, 1H),6.3 (d, 1H), 6.2 (s, 1H), 4.5 (s, 2H), 4.0 (s, 3H), 2.4 (s, 3H), LC-MS(ESI): Calculated mass: 492.53; Observed mass: 493.1 [M+H]⁺ (rt: 1.415min).

Example 791-cyclopentyl-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)urea

The compound was prepared from the compound of Example 74(a) using theprocedures of Example 78. ¹H NMR (300 MHz, CD₃OD): δ 8.7 (s, 1H), 8.6(s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.6-7.7 (m, 5H), 7.5(s, 1H), 6.9 (d, 1H), 6.3 (s, 2H), 4.0 (s, 3H), 2.4 (s, 3H), 1.4-1.9 (m,8H). LC-MS (ESI): Calculated mass: 480.56; Observed mass: 481.2 [M+H]⁺(rt: 1.517 min).

Example 80N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methyl-furan-2-yl)phenyl)morpholine-4-carboxamide

The compound was prepared from the compound of Example 74(a) using theprocedures of Example 78. ¹H NMR (300 MHz, CD₃OD): δ 8.5 (s, 1H), 8.0(s, 1H), 7.95 (s, 1H), 7.9 (s, 1H), 7.8 (s, 2H), 7.6-7.7 (m, 3H), 7.5(s, 1H), 6.8 (d, 1H), 6.2 (s, 1H), 4.0 (s, 3H), 2.4 (s, 3H), 3.6 (t,4H), 3.8 (t, 4H). LC-MS (ESI): Calculated mass: 482.53; Observed mass:483.1 [M+H]⁺ (rt: 0.814 min).

Example 81N-(3-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)acetamide

The compound was prepared from the compound of Example 73(e) using theprocedures of Example 73. ¹H NMR (300 MHz, DMSO-d₆): δ 10.1 (s, 1H), 8.6(s, 1H), 8.4 (s, 1H), 7.7-8.0 (m, 4H), 7.6 (m, 3H), 7.0 (d, 1H), 6.8 (d,1H), 6.2 (d, 1H), 4.2 (t, 2H), 3.8 (t, 2H), 2.4 (s, 3H), 2.2 (s, 3H).LC-MS (ESI): Calculated mass: 441.48; Observed mass: 442.1[M+H]⁺ (rt:0.436 min).

Example 82N-(3-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)acetamide

The compound was prepared from the compound of Example 73(e) using theprocedures of Example 73. ¹H NMR (300 MHz, CD₃OD): δ; 9.5 (s, 1H), 8.3(s, 1H), 8.1 (m, 3H), 7.95 (m, 4H), 7.7 (m, 1H), 6.8 (d, 1H), 6.2 (s,1H), 4.20 (m, 2H), 3.7 (m, 2H), 3.0 (s, 6H), 2.4 (s, 3H), 2.2 (s, 3H).LC-MS (ESI): Calculated mass: 468.55; Observed mass: 469.5 [M+H]⁺ (rt:0.179 min).

Example 83N-(3-(5-methylfuran-2-yl)-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide

The compound was prepared from the compound of Example 73(e) using theprocedures of Example 73. ¹H NMR (300 MHz, CD₃OD): δ; 9.5 (s, 1H), 8.3(s, 1H), 8.1 (m, 3H), 7.95 (m, 3H), 7.7 (m, 1H), 6.8 (d, 1H), 6.2 (d,1H), 4.70 (t, 2H), 4.0 (m, 3H), 3.7 (t, 2H), 3.50 (m, 3H), 2.4 (s, 4H),2.2 (s, 4H). LC-MS (ESI): Calculated mass: 510; Observed mass:511.2[M+H]⁺ (rt: 0.277 min).

Example 84N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)-phenyl)acetamide

To a solution of the compound of Example 73(e) (0.1 g, 0.243 mmol) inDMF (5 ml) were added pyrazole (0.022 g, 0.0317 mmol, 1.3 eq.),copper(I) oxide (0.01 g, 0.1 eq.) and cesium carbonate (0.158 g, 0.0487mmol, 2.0 eq.) and the mixture was heated at 110° C. for 48 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by preparative HPLC to givethe product in 68% yield (0.02 g). ¹H NMR (300 MHz, DMSO-d₆): δ; 9.3 (s,1H), 8.4 (s, 1H), 8.3 (s, 1H), 7.8-8.1 (m, 4H), 7.6-7.7 (m, 3H), 6.80(d, 1H), 6.6 (t, 1H), 6.2 (d, 1H), 2.4 (s, 3H), 2.2 (s, 3H), LC-MS(ESI): Calculated mass: 397.43; Observed mass: 398.3 [M+H]⁺ (rt: 1.382min).

Example 85N-(3-(5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)-phenyl)acetamide

The compound was prepared from the compound of Example 73(e) using theprocedures of Example 84. ¹H NMR (300 MHz, DMSO-d₆): δ 9.5 (s, 1H), 9.0(m, 1H), 8.2 (m, 2H), 8.0 (s, 2H), 7.8 (m, 4H), 7.6 (s, 1H), 6.80 (d,1H), 6.2 (d, 1H), 2.4 (s, 3H), 2.2 (s, 3H), LC-MS (ESI): Calculatedmass: 397.43; Observed mass: 398.3 [M+H]⁺ (rt: 0.179 min).

Example 86N-(3-(5-(4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(5-methylfuran-2-yl)phenyl)acetamide

The compound was prepared from the compound of Example 73(e) using theprocedures of Example 84. ¹H NMR (300 MHz, DMSO-d₆): δ; 10.4 (s, 1H),9.3 (s, 1H), 8.8 (s, 1H), 8.4 (d, 2H), 7.8-8.1 (m, 4H), 7.6 (s, 1H),6.80 (d, 1H), 6.2 (d, 1H), 2.4 (s, 3H), 2.2 (s, 3H), LC-MS (ESI):Calculated mass: 398.42; Observed mass: 399.2 [M+H]⁺ (rt: 0.914 min).

Example 87N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamidea) 1-(3,5-Dinitro-phenyl)-1H-pyrrole

A solution of 3,5-dinitroaniline (10 g, 54.644 mmol) and2,5-dimethoxytetrahydrofuran (18.05 g, 136.61 mmol, 2.5 eq.) in aceticacid (122 ml) was heated to 100° C. for 16 h. Completion of reaction wasmonitored by TLC. Then the mixture was brought to RT and poured intoice-cold water. The precipitate was filtered, washed with water (150 ml)and dried to give the product in 54% yield (8.2 g). LC-MS (ESI):Calculated mass: 233.18; Observed mass: 233.04 [M+H]⁺ (rt: 1.667 min).

b) 3-Nitro-5-pyrrol-1-yl-phenylamine

To a solution of 1-(3, 5-dinitro-phenyl)-1H-pyrrole (8.2 g, 35.19 mmol)and pyridine (10 ml) in ethanol (100 ml), at 80° C., was added a 20%aqueous solution of ammonium sulfide (38.4 ml, 140.76 mmol, 4.0 eq.) inwater (10 ml). The mixture was stirred at the same temperature for 4 h.The the mixture was quenched with ice water (200 ml) and theprecipitated solid was filtered. The filtered solid was dried undervacuum to afford the product in 98% yield (7.0 g).

c) N-(3-Nitro-5-pyrrol-1-yl-phenyl)-acetamide

Acetic anhydride (7.0 ml) was added to 3-nitro-5-pyrrol-1-yl-phenylamine(7.0 g, 34.48 mmol). The mixture was stirred for 30 min at RT andsubsequently quenched by the addition of crushed ice. The precipitateformed was filtered and was washed with cold water to obtain off-whitesolid. The solid was dried under high vacuum to give the product in 89%yield (7.52 g). LC-MS (ESI): Calculated mass: 245.23; Observed mass:244.1 [M−H]⁺ (rt: 0.24 min).

d) N-(3-Amino-5-pyrrol-1-yl-phenyl)-acetamide

To a solution of N-(3-nitro-5-pyrrol-1-yl-phenyl)acetamide (7.51 g,30.61 mmol) in ethanol (100 ml), were added iron powder (4.273 g, 76.53mmol, 2.5 eq.) and a solution of calcium chloride (8.49 g, 76.53 mmol,2.5 eq.) in water (100 ml). The mixture was stirred at 80° C. for 2 hand then filtered through a pad of celite. The celite pad was washedwith ethyl acetate (200 ml) and the combined organic layer was washedwith water (100 ml) and brine (25 ml). The solvent was evaporated andthe residue was purified by column chromatography (20% ethyl acetate inhexanes) to give the compound in 87% yield (5.7 g). ¹H NMR (300 MHz,DMSO-d₆): δ 9.9 (s, 1H), 8.25 (s, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.05(d, 1H), 6.8 (s, 1H), 6.5 (m, 1H), 6.3 (m, 1H), 5.15 (s, 2H), 2.02 (s,3H).

e) N-(3-(4-bromo-2-nitrophenylamino)-5-(1H-pyrrol-1-yl) phenyl)acetamide

To a solution of N-(3-amino-5-pyrrol-1-yl-phenyl)acetamide (5 g, 23.23mmol) in anhydrous DMF (5 ml), 4-bromo-1-fluoro-2-nitrobenzene (5.11 g,23.23 mmol) and potassium fluoride (1.35 g, 23.23 mmol) were added. Themixture was stirred at 110° C. for overnight. Then the mixture wasbrought to RT and DMF was removed under vacuum. Residue was subjected toflash column chromategraphy (50% ethyl acetate in hexanes) to get thecompound in 63% yield (6.1 g).

f) N-(3-(2-amino-4-bromophenylamino)-5-(1H-pyrrol-1-yl) phenyl)acetamide

To a solution of the compound of Example 87(e) (6.0 g, 14.45 mmol) inethanol (50 ml), iron powder (2.02 g, 36.12 mmol, 2.5 eq.) and calciumchloride (4.01 g, 36.12 mmol, 2.5 eq.) with 50 ml water were added. Themixture was stirred at 80° C. for 2 h and then filtered through a pad ofcelite. The celite pad was washed with ethyl acetate (100 ml) and thecombined organic layer was washed with water (50 ml) and brine (25 ml).The solvent was evaporated and the residue was purified by columnchromatography (20% ethyl acetate in hexanes) to give the compound in86% yield (4.8 g). LC-MS (ESI): Calculated mass: 385.26; Observed mass:385 [M+H]⁺ (rt: 1.659 min).

g) N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(l H-pyrrol-1-yl) phenyl)acetamide

Formic acid (12 ml) was added to the compound of Example 87(f) (4 g,10.38 mmol) at RT and the mixture was heated at 100° C. for 2 h. Theformic acid was removed under reduced pressure and the residue waspurified over flash column chromatography (3% methanol in chloroform) toafford the product in 76% yield (3.1 g). LC-MS (ESI): Calculated mass:395.25; Observed mass: 396.8 [M+H]⁺ (RT: 1.55 min).

h)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl) acetamide

To a solution of the compound of Example 87(g) (2.0 g, 5.06 mmol) in1,2-methoxyethane (50 ml),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.58 g, 7.59 mmol, 1.5 eq.), sodium carbonate (1.34 g, 12.65 mmol, 2.5eq.) and water (5.0 ml) were added and the mixture was degassed for 15min (N₂ bubbling). Pd(PPh₃)₄ (2.92 g, 2.53 mmol, 0.5 eq.) was added andthe mixture was heated at 100° C. for 2 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified column chromatography afford the compound in 60%yield (1.2 g). ¹H-NMR (300 MHz, CD₃OD): δ 8.53 (s, 1H), 8.0 (s, 1H), 7.9(s, 1H), 7.82 (m, 2H), 7.79 (m, 1H), 7.7 (d, 1H), 7.6 (m, 1H), 7.48 (m,1H), 7.29 (m, 2H), 6.31 (m, 2H), 3.95 (s, 3H), 2.15 (s, 3H); LC-MS(ESI): Calculated mass: 396.44; Observed mass: 396.8 [M+H]⁺ (rt: 0.63min).

Example 88N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)methanesulfonamidea)3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

A mixture of 20% sodium hydroxide (5 ml) and the compound of Example 87(1.15 g, 2.9 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. Themixture was diluted with ethyl acetate (100 ml) and the organic layerwas washed with water (50 ml) and brine (25 ml). The solvent was removedunder reduced pressure and the crude was purified by columnchromatography over silica gel to give the product in 68% yield (0.7 g).

b)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)methanesulfonamide

To a solution of the compound of Example 88(a) (70 mg, 0.198 mmol) inDCM (1 ml) were added pyridine (0.5 ml) and methanesulfonyl chloride (27mg, 0.237 mmol, 1.2 eq.) and the mixture was stirred at RT for 12 h.Pyridine was removed under reduced pressure and the crude was purifiedby preparative HPLC to give the product in 12% yield (10 mg). ¹H NMR(300 MHz, DMSO-d₆): δ: 10.2 (s, 1H), 8.7 (s, 1H), 8.21 (s, 1H), 7.99 (d,2H), 7.7-7.61 (m, 3H), 7.45 (t, 2H), 7.38 (d, 2H), 6.33 (t, 2H), 3.88(s, 3H), 3.2 (s, 3H); LC-MS (ESI): Calculated mass: 432.5; Observedmass: 433.1 [M+H]⁺ (rt: 0.88 min).

Example 89N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 87 using theprocedures of Example 88 and cyclopropane sulfonyl chloride. ¹H-NMR (300MHz, DMSO-d₆): δ 10.2 (s, 1H), 8.71 (s, 1H), 8.2 (s, 1H), 7.99 (m, 1H),7.95 (s, 1H), 7.68-7.59 (m, 3H), 7.44-7.41 (m, 4H), 6.31 (m, 2H), 3.95(s, 3H), 2.95 (m, 1H), 1.0 (m, 4H); LC-MS (ESI): Calculated mass:458.54; Observed mass: 459.2 [M+H]⁺ (rt: 1.29 min).

Example 90N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)benzenesulfonamide

The compound was prepared from the compound of Example 87 using theprocedures of Example 88. ¹H-NMR (300 MHz, CD₃OD): δ 8.35 (s, 1H), 7.93(s, 1H), 7.83-7.78 (m, 4H), 7.58-7.55 (m, 1H), 7.51-7.47 (m, 3H), 7.36(t, 1H), 7.32 (d, 1H), 7.21 t, 1H), 7.14 (t, 1H), 7.12-7.11 (m, 2H),6.22 (t, 2H), 3.9 (s, 3H); LC-MS (ESI): Calculated mass: 494.57;Observed mass: 495 [M+H]⁺ (rt: 1.71 min).

Example 911-(furan-2-ylmethyl)-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)urea

To a solution of the compound of Example 88(a) (70 mg, 0.198 mmol) inDCM (1 ml) at 0° C. were added TEA (triethylamine) (0.055 ml, 0.396mmol, 2.0 eq.) and 2-(isocyanatomethyl)furan (29 mg, 0.237 mmol, 1.2eq.). The mixture was stirred at RT for 16 h. The solvent was removedunder reduced pressure and the residue was purified by preparative HPLCto afford the compound in 40% yield (38 mg). ¹H-NMR (300 MHz, CD₃OD): δ9.0 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.81-7.74 (m,3H), 7.63 (s, 1H), 7.44 (m, 2H), 7.3 (m, 2H), 6.36-6.31 (m, 4H), 4.41(s, 2H), 3.96 (s, 3H); LC-MS (ESI): Calculated mass: 477.52; Observedmass: 478.1 [M+H]⁺ (rt: 1.393 min).

Example 921-cyclopentyl-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)urea

The compound was prepared from the compound of Example 87 using theprocedures of Example 91. ¹H-NMR (300 MHz, CD₃OD): δ 9.52 (s, 1H), 8.16(s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.88-7.84 (m, 3H), 7.65 (s, 1H),7.47 (s, 1H), 7.3 (m, 2H), 6.35 (m, 2H), 4.1 (m, 1H), 3.95 (s, 3H), 2.05(m, 2H), 1.8-1.6 (m, 4H), 1.51-1.48 (m, 2H); LC-MS (ESI): Calculatedmass: 465.55; Observed mass: 466.1 [M+H]⁺ (rt: 1.45 min).

Example 93N-(3-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

The compound was prepared from the compound of Example 87(g) using theprocedures of Example 87. ¹H-NMR (300 MHz, CD₃OD): δ 8.42 (s, 1H), 8.0(s, 1H), 7.82-7.8 (m, 2H), 7.75 (s, 1H), 7.65 (s, 1H), 7.6 (d, 1H), 7.51(d, 1H), 7.38 (s, 1H), 7.19 (m, 2H), 6.21 (m, 2H), 4.32 (t, 2H), 3.0 (t,2H), 2.4 (s, 6H), 2.08 (s, 3H); LC-MS (ESI): Calculated mass: 453.23;Observed mass: 453.9 [M+H]⁺ (rt: 0.112 min).

Example 94N-(3-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)benzenesulfonamide

The compound was prepared from the compound of Example 93 using theprocedures of Example 88. ¹H-NMR (300 MHz, DMSO-d₆): δ 10.91 (s, 1H),8.66 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.91-7.89 (m,2H), 7.7-7.59 (m, 5H), 7.36-7.29 (m, 4H), 7.22 (m, 1H), 6.32 (t, 2H),4.57 (t, 2H), 3.64 (m, 2H), 2.86 (d, 6H); LC-MS (ESI): Calculated mass:551.66; Observed mass: 552.2 [M+H]⁺ (rt: 0.54 min).

Example 95N-(3-(5-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)-phenyl)acetamide

The compound was prepared using the procedures of Example 87. ¹H-NMR(300 MHz, CD₃OD): δ 9.0 (s, 1H), 8.37 (d, 1H), 7.96 (dd, 1H), 7.92 (s,1H), 7.89-7.87 (m, 1H), 7.78 (d, 1H), 7.71 (t, 2H), 7.68-7.65 (m, 1H),7.49 (t, 1H), 7.2 (t, 2H), 6.85 (d, 1H), 6.25 (t, 2H), 3.89 (s, 3H), 2.1(s, 3H); LC-MS (ESI): Calculated mass: 423.47; Observed mass:424.1[M+H]⁺ (rt: 1.518 min).

Example 96 N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrrol-1-yl)-phenyl)acetamide

To a solution of the compound of Example 87(g) (2.0 g, 5.06 mmol) in DMF(50 ml) were added pyrazole (0.69 g, 10.12 mmol, 2.0 eq.), copper(I)oxide (0.145 g, 1.01 mmol, 0.2 eq.) and cesium carbonate (3.3 g, 10.12mmol, 2.0 eq.) and the mixture was heated at 110° C. for 16 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by column chromatography togive the product in 78% yield (1.5 g). ¹H-NMR (300 MHz, DMSO-d₆): δ 10.2(s, 1H), 8.79 (s, 1H), 8.61 (d, 1H), 8.24 (d, 1H), 7.94-7.91 (m, 1H),7.87-7.81 (m, 3H), 7.76 (d, 1H), 7.64-7.63 (m, 1H), 7.43-7.42 (m, 2H),6.57 (t, 1H), 6.33 (m, 2H), 2.13 (s, 3H); LC-MS (ESI): Calculated mass:382.42; Observed mass: 383.1 [M+H]⁺ (rt: 1.376 min).

Example 97N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)-phenyl)ethanesulfonamidea)3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

A mixture of 10% NaOH (5 ml) and the compound of Example 96 (1.45 g,3.79 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. The mixturewas diluted with ethyl acetate (100 ml) and the organic layer was washedwith water (50 ml) and brine (25 ml). The solvent was removed underreduced pressure and the residue was purified by column chromatographyover silica gel to give the product in 85% yield (1.1 g).

b)N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)-phenyl)ethanesulfonamide

To a solution of the compound of Example 97(a) (70 mg, 0.206 mmol) inDCM (2 ml) were added pyridine (0.033 ml, 0.411 mmol, 2.0 eq.) andethanesulfonyl chloride (32 mg, 0.247 mmol, 1.2 eq.) and the mixture wasstirred at RT for 12 h. Pyridine was removed under reduced pressure andthe residue was purified by preparative HPLC to afford the product in63% yield (56 mg). ¹H-NMR (300 MHz, DMSO-d₆): δ 10.35 (s, 1H), 8.83 (s,1H), 8.62 (d, 1H), 8.26 (d, 1H), 7.95 (dd, 1H), 7.82-7.78 (m, 2H), 7.69(s, 1H), 7.46-7.42 (m, 4H), 6.58 (t, 1H), 6.35 (t, 2H), 3.34-3.32 (m,2H), 1.28 (t, 3H); LC-MS (ESI): Calculated mass: 432.5; Observed mass:433.2 [M+H]⁺ (rt: 1.43 min).

Example 98N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)-phenyl)propane-2-sulfonamide

The compound was prepared from the compound of Example 96 using theprocedures of Example 87. ¹H-NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H),8.81 (s, 1H), 8.6 (d, 1H), 8.25 (d, 1H), 7.95-7.92 (m, 1H), 7.79-7.76(m, 2H), 7.66 (m, 1H), 7.43 (m, 4H), 6.57-6.56 (m, 1H), 6.34-6.33 (m,2H), 3.53-3.5 (m, 1H), 1.31 (d, 6H); LC-MS (ESI): Calculated mass:446.52: Observed mass: 447.2 [M+H]⁺ (rt: 1.5 min).

Example 99N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamidea) N-(3-(4-iodo-2-nitrophenylamino)-5-(1H-pyrrol-1-yl)phenyl)acetamide

A solution of N-(3-amino-5-pyrrol-1-yl-phenyl)acetamide of Example 87(d)(5.0 g, 18.72 mmol), 1-fluoro-4-iodo-2-nitrobenzene (4.02 g, 18.72 mmol,1.0 eq.) and potassium fluoride (1.08 g, 18.72 mmol, 1.0 eq.) in DMF (30ml) was heated at 130° C. for 5 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (60-120 silica gel, 50%ethyl acetate in hexane) to give the product in 49% yield (4.3 g).

b) N-(3-((2-amino-4-iodophenyl)amino)-5-(1H-pyrrol-1-yl)phenyl)acetamide

To a solution of the compound of Example 99(a) (0.5 g, 1.08 mmol) in THF(30 ml) were added a solution of ammonium chloride (0.289 g, 5.41 mmol,5 eq.) in water (5 ml) and zinc (0.354 g, 5.41 mmol, 5 eq.). The mixturewas stirred at RT for 0.5 h and filtered. The filtrate was diluted withwater and extracted as in Example 1(d). The solvent was distilled off toafford the product in 75% yield (0.35 g). ¹H NMR (300 MHz, DMSO-d₆): δ9.88 (s, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.09-7.06 (m, 3H), 6.84-6.8(m, 3H), 6.51 (m, 1H), 6.22 (t, 2H), 5.04 (br s, 2H), 2.0 (s, 3H).

c) N-(3-(5-iodo-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl) phenyl)acetamide

A mixture of the compound of Example 99(b) (0.35 g, 0.81 mmol) andformic acid (10 ml) was heated at 100° C. for 30 min. The formic acidwas distilled off under reduced pressure and the residue was dissolvedin ethyl acetate. The ethyl acetate layer was washed with water, brineand dried over sodium sulphate. The solvent was distilled off to affordthe product in 84% yield (0.3 g). ¹H NMR, 300 MHz: (DMSO-d₆): δ 10.4 (s,1H), 8.7 (s, 1H), 8.18 (s, 1H), 7.82 (s, 2H), 7.67-7.54 (m, 3H), 7.4 (s,2H), 6.32 (m, 2H), 2.05 (s, 3H).

d) N-(3-(1H-pyrrol-1-yl)-5-(5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl) phenyl) acetamide

A solution of the compound of Example 99(c) (3.0 g, 7.4 mmol) inDMF-Et₃N (1:1; 60 ml) was degassed by N₂ bubbling for 15 min. Pd(PPh₃)₄(1.2 g, 11.9 mmol, 0.1 eq.), copper(I) iodide (0.2 g, 11.9 mmol, 0.1eq.) and ethynyltrimethylsilane (2.2 ml, 49.2 mmol, 2 eq.) were addedsequentially and the mixture was stirred for 12 h at RT. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offand the residue was purified by column chromatography (60-120 silicagel, 60% ethyl acetate in hexane) to give the product in 71% yield (2.0g). ¹HNMR, 300 MHz: (DMSO-d₆): δ 10.4 (s, 1H), 8.85 (s, 1H), 7.9-7.8 (m,2H), 7.75-7.5 (m, 6H), 7.45 (t, 2H), 2.05 (s, 3H), 0.2 (s, 9H); LC-MS(ESI): Calculated mass: 412.56; Observed mass: 413 [M+H]⁺ (rt: 1.55min).

e)N-(3-(5-ethynyl-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

To a solution of the compound of Example 99(d) (2.0 g, 4.85 mmol) in THFat 0° C. was added TBAF (1M in THF; 2.0 ml, 9.7 mmol, 2 eq.) and themixture was stirred for 0.5 h. The mixture was filtered over a pad ofsilica and distilled to give the product in 96% yield (1.6 g). LC-MS(ESI): Calculated mass: 340.38; Observed mass: 341.1 [M+H]⁺ (rt: 1.518min).

f)N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

A mixture of the compound of Example 99(e) (1.0 g, 29.4 mmol), sodiumazide (0.19 g, 29.4 mmol, 1.0 eq.), methyl iodide (0.4 g, 29.4 mmol, 1.0eq.), sodium ascorbate (0.6 g, 29.4 mmol, 1.0 eq.) and copper sulfatepentahydrate (0.36 g, 14.7 mmol, 0.5 eq.) in DMSO, DCM and water (1:1:1,15:12:12 ml) was stirred for 12 h at RT. The mixture was quenched withwater and the precipitate formed was filtered and dried to give thecrude product which was purified by preparative HPLC to give the productin 15% yield (0.02 g). LC-MS (ESI): Calculated mass: 397.43; Observedmass: 398.1 [M+H]⁺ (rt: 0.453 min).

Example 100N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)methanesulfonamidea)3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

A mixture of 20% sodium hydroxide (5 ml) and the compound of Example 99(1.0 g, 2.52 mmol) in 10 ml ethanol was heated at 100° C. for 3 h. Themixture was diluted with ethyl acetate (100 ml) and the organic layerwas washed with water (50 ml) and brine (25 ml). The solvent was removedunder reduced pressure and the residue was purified by columnchromatography over silica gel to afford the product in 73% yield (0.65g). LC-MS (ESI): Calculated mass: 355.4; Observed mass: 356.3 [M+H]⁺(rt: 0.49 min).

b)N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrrol-1-yl)phenyl)methanesulfonamide

To a solution of the compound of Example 100(a) (100 mg, 0.281 mmol) inDCM (5 ml) were added pyridine (45 mg, 0.563 mmol, 2.0 eq.) andmethanesulfonyl chloride (26 mg, 0.225 mmol, 0.8 eq.) and the mixturewas stirred at RT for 12 h. Pyridine was removed under reduced pressureand the residue was purified by preparative HPLC to afford the productin 7% yield (8 mg). ¹H NMR, 300 MHz: (DMSO-d₆): δ 10.33 (s, 1H), 9.01(s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.97-7.94 (m, 1H), 7.83 (d, 1H),7.71 (s, 1H), 7.46-7.42 (m, 4H), 6.35-6.34 (m, 2H), 4.12 (s, 3H), 3.21(s, 3H); LC-MS (ESI): Calculated mass: 433.49; Observed mass: 434.3[M+H]⁺ (rt: 0.67 min).

Example 101N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamide

The compound was prepared from the compound of Example 99 using theprocedures of Example 100. ¹H NMR, 300 MHz: (DMSO-d₆): δ 10.37 (s, 1H),8.97 (s, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.95-7.93 (m, 1H), 7.8 (d,1H), 7.67 (m, 1H), 7.45-7.42 (m, 4H), 6.34 (t, 2H), 4.2 (s, 3H), 2.4 (m,2H), 1.2 (d, 3H); LC-MS (ESI): Calculated mass: 447.51; Observed mass:449.1 [M+H]⁺ (rt: 0.97 min).

Example 102N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 99 using theprocedures of Example 100 and cyclopropane sulfonyl chloride. ¹H NMR,300 MHz: (DMSO-d₆): δ 10.3 (s, 1H), 8.8 (s, 1H), 8.61 (s, 1H), 8.25 (s,1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.46-7.43 (m, 4H), 6.34(t, 2H), 4.12 (s, 3H), 2.94 (m, 1H), 1.04-1.02 (m, 4H); LC-MS (ESI):Calculated mass: 459.52; Observed mass: 460.1 [M+H]⁺ (rt: 1.22 min).

Example 103N-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)benzenesulfonamide

The compound was prepared from the compound of Example 99 using theprocedures of Example 100. ¹H NMR, 300 MHz: (DMSO-d₆): δ 10.91 (s, 1H),8.69 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.92-7.89 (m, 3H), 7.67-7.62(m, 4H), 7.37-7.32 (m, 4H), 7.20 (s, 1H), 6.32 (d, 2H), 4.11 (s, 3H);LC-MS (ESI): Calculated mass: 495.56; Observed mass: 496.1 [M+H]⁺ (rt:1.42 min).

Example 1041-(furan-2-ylmethyl)-3-(3-(5-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-5-(lH-pyrrol-1-yl)phenyl)urea

To a solution of the compound of Example 100(a) (100 mg, 0.281 mmol) inDCM (10 ml) at 0° C. was added 2-(isocyanatomethyl)furan (35 mg, 0.281mmol, 1.0 eq.) and the mixture was stirred at RT for 16 h. The solventwas removed under reduced pressure and the residue was purified bypreparative HPLC to give the compound in 13% yield (18 mg). ¹H NMR, 300MHz: (DMSO-d₆): δ 9.05 (s, 1H), 8.8 (s, 1H), 8.6 (s, 1H), 8.24 (s, 1H),7.92-7.9 (m, 1H), 7.81 (d, 1H), 7.72-7.60 (m, 4H), 7.48-7.41 (m, 3H),6.89 (t, 1H), 6.41 (m, 1H), 6.32-6.28 (m, 2H), 4.33 (d, 2H), 4.12 (s,3H); LC-MS (ESI): Calculated mass: 478.51; Observed mass: 479.2 [M+H]⁺(rt: 1.39 min).

Example 105N-(3-(5-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

A mixture of the compound of Example 99(e) (100 mg, 0.294 mmol),4-(2-azidoethyl)morpholine (55 mg, 0.353 mmol, 1.2 eq.), sodiumascorbate (58 mg, 0.294 mmol, 1.0 eq.) and copper sulfate pentahydrate(37 mg, 0.147 mmol, 0.5 eq.) in DMSO, DCM and water (1:1:1, 3 ml) wasstirred for 12 h at RT. The mixture was quenched with water and theprecipitate formed was filtered and dried to give the crude productwhich was purified by preparative HPLC to give the product in 7% yield(10 mg). ¹H NMR, 300 MHz: (DMSO-d₆): δ 10.46 (s, 1H), 8.83 (s, 1H), 8.73(s, 1H), 8.28 (s, 1H), 7.92 (m, 2H), 7.84-7.81 (m, 2H), 7.63 (s, 1H),7.43-7.42 (m, 2H), 6.34 (m, 2H), 4.82 (t, 2H), 4.01 (m, 4H), 3.7 (m,2H), 2.51-2.43 (m, 4H), 2.05 (s, 3H); LC-MS (ESI): Calculated mass:496.56; Observed mass: 497 [M+H]⁺ (rt: 0.08 min). Example 106.

N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)-acetamidea) N-(3-(4-formyl-2-nitrophenylamino)-5-(1H-pyrrol-1-yl)phenyl)acetamide

A solution of the compound of Example 87(d) (5.5 g, 25.7 mmol),4-fluoro-3-nitrobenzaldehyde of Intermediate Example 4 (3.86 g, 25.7mmol, 1.0 eq.) and potassium fluoride (1.49 g, 25.7 mmol, 1.0 eq.) inDMF (5 ml) was heated at 130° C. for 4 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (60-120 silica gel, 40%ethyl acetate in hexane) to give the product in 38% yield (3.58 g). ¹HNMR (300 MHz, DMSO-d₆): δ 10.05 (s, 1H), 9.86 (s, 1H), 8.71 (s, 1H),7.95 (d, 1H), 7.67 (m, 2H), 7.50 (s, 1H), 7.32-7.29 (m, 5H), 6.29 (s,1H), 2.08 (s, 3H).

b)N-(3-(2-nitro-4-(oxazol-5-yl)phenylamino)-5-(1H-pyrrol-1-yl)phenyl)acetamide

To a solution of the compound of Example 106(a) (2.5 g, 6.88 mmol) inmethanol (15 ml) was added potassium carbonate (1.04 g, 7.57 mmol, 1.1eq.) and the mixture was stirred for 10 min at RT. Toluenesulfonylmethylisocyanide (1.48 g, 7.57 mmol, 1.1 eq.) was added and the mixture wasrefluxed for 4 h. The solvent was distilled off and water was added tothe crude. The mixture was extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by column chromatography(60-120 silica gel, 70% ethyl acetate in hexane) to give the product in57% yield (1.58 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.05 (d, 1H), 10.32(d, 1H), 9.87 (s, 1H), 7.81 (s, 1H), 7.98-7.92 (m, 1H), 7.85-7.60 (m,3H), 7.55 (s, 1H), 7.32-7.29 (m, 4H), 7.29 (s, 1H), 2.08 (s, 3H).

c)N-(3-(2-amino-4-(oxazol-5-yl)phenylamino)-5-(1H-pyrrol-1-yl)phenyl)acetamide

To a solution of the compound of Example 106(b) (1.58 g, 3.9 mmol) inmethanol (30 ml) and ethylacetate (15 ml) was added 10% Pd/C (300 mg,0.2 eq.) and the reaction vessel was purged with nitrogen gas for 5 min.The mixture was then hydrogenated with H₂ balloon for 12 h. The mixturewas filtered through a pad of celite and the filtrate was concentratedto afford the compound in 68% yield (1.0 g).

d)N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)-acetamide

A mixture of the compound of Example 106(c) (0.4 g, 1.07 mmol) andformic acid (4 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and the residue was purified bypreparative HPLC to give the product in 12% yield (50 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.43 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 8.17 (s,1H), 7.87-7.77 (m, 5H), 7.63 (s, 1H), 7.42 (t, 2H), 6.34 (t, 2H), 2.13(s, 3H); LC-MS (ESI): Calculated mass: 383.40; Observed mass: 384.1[M+H]⁺ (rt: 1.108 min).

Example 107 N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrrol-1-yl)phenyl)-propane-2-sulfonamide a)3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

To a solution of the compound of Example 106 (800 mg, 2.1 mmol) inethanol (15 ml) was added aqueous solution of NaOH (0.72 g, 18.06 mmol,8.6 eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 70% yield (0.5 g).

b)N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)-propane-2-sulfonamide

To a solution of the compound of Example 107(a) (80 mg, 0.23 mmol) inDCM (2 ml) was added pyridine (37 mg, 0.47 mmol, 2.0 eq.) followed bypropane-2-sulfonyl chloride (39 mg, 0.28 mmol, 1.2 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 14% yield (14 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.29 (s, 1H), 8.80 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H),7.82-7.86 (m, 3H), 7.68 (s, 1H), 7.46-7.40 (m, 4H), 6.34 (t, 2H), 3.30(m, 1H), 2.51-2.50 (m, 6H); LC-MS (ESI): Calculated mass: 447.51;Observed mass: 448.1 [M+H]⁺ (rt: 2.001 min).

Example 108N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)-cyclopropanesulfonamide

The compound was prepared from the compound of Example 106 using theprocedures of Example 107 and cyclopropane sulfonyl chloride. ¹H NMR(300 MHz, DMSO-d₆): δ 10.35 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.22(s, 1H), 7.82 (d, 3H), 7.74-7.35 (m, 1H), 7.5-7.45 (m, 4H), 6.39 (t,2H), 3.04-2.95 (m, 1H), 1.08-1.07 (m, 4H); LC-MS (ESI): Calculated mass:445.49; Observed mass: 446.1 [M+H]⁺ (rt: 1.43 min).

Example 109N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamide

The compound was prepared from the compound of Example 87 using theprocedures of Example 88. ¹H NMR (300 MHz, DMSO-d₆): δ 10.3 (s, 1H),8.67 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.67-7.61 (m, 3H),7.43-7.39 (m, 4H), 6.38 (s, 2H), 3.88 (s, 3H), 3.32 (quartet, 2H), 1.27(t, 3H); LC-MS (ESI): Calculated mass: 446.52; Observed mass: 447.1[M+H]⁺ (rt: 1.25 min).

Example 110N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)propane-2-sulfonamide

The compound was prepared from the compound of Example 87 using theprocedures of Example 88. ¹H NMR (400 MHz, DMSO-d₆): δ 10.34 (s, 1H),8.89 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.69-7.65 (m,3H), 7.44-7.41 (m, 4H), 7.64 (d, 2H), 3.89 (s, 3H), 3.51-3.50 (m, 1H),1.31 (d, 6H); LC-MS (ESI): Calculated mass: 460.55; Observed mass: 461.1[M+H]⁺ (rt: 1.377 min).

Example 111N-(3-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

The compound was prepared using the procedures of Example 87. ¹H NMR(300 MHz DMSO-d₆): δ 10.45 (s, 1H), 8.96 (s, 1H), 8.34 (s, 1H), 8.04 (s,1H), 7.98 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.72-7.68 (m, 2H), 7.64(s, 1H), 7.42 (t, 2H), 6.34 (t, 2H), 4.68-4.57 (m, 1H), 2.14 (s, 3H),2.08-1.93 (m, 4H), 1.87-1.73 (m, 2H), 1.72-1.60 (m, 2H); LC-MS (ESI):Calculated mass: 450.53; Observed mass: 451.2 [M+H]⁺ (rt: 1.509 min).

Example 112N-(3-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-5-(lH-pyrrol-1-yl)phenyl)acetamide

A mixture of the compound of Example 99(e) (0.3 g, 0.88 mmol),4-azido-2-methylbutan-2-ol of Intermediate Example 6 (0.17 g, 1.06 mmol,1.2 eq.), sodium-(L)-ascorbate (0.17 g, 0.88 mmol, 1.0 eq.) and coppersulfate pentahydrate (0.11 g, 0.44 mmol, 0.5 eq.) in DCM (2 ml), DMSO (2ml) and water (2 ml) was stirred for 12 h at RT. The mixture wasquenched with water and the precipitate was filtered and dried. Thecrude product was purified by preparative HPLC to give the product in48% yield (0.2 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.86 (s,1H), 8.68 (s, 1H), 8.23 (s, 1H), 7.93-7.77 (m, 4H), 7.62 (s, 1H), 7.40(t, 2H), 6.31 (t, 2H), 4.70 (t, 2H), 3.40 (br s, 1H), 2.48 (t, 2H), 2.11(s, 3H), 1.16 (s, 6H); LC-MS (ESI): Calculated mass: 469.54; Observedmass: 470.2 [M+H]⁺ (rt: 0.666 min).

Example 113N-(3-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamidea)4-(4-(1-(3-amino-5-(1H-pyrrol-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)-2-methylbutan-2-ol

To a solution of the compound of Example 112 (150 mg, 0.32 mmol) inethanol (10 ml) was added aqueous solution of NaOH (160 mg, 4 mmol, 12.5eq.) and the mixture was heated at 80° C. for 2 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 58% yield (80 mg).

b)N-(3-(5-(1-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamide

To a solution of the compound of Example 113(a) (100 mg, 0.234 mmol) inDCM (5 ml) was added pyridine (36 mg, 0.47 mmol, 2 eq.) followed byethanesulfonyl chloride (23 mg, 0.187 mmol, 0.8 eq.). The mixture wasstirred for 2 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 10% yield (12 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.35 (s, 1H), 8.88 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H),7.93 (dd, 1H), 7.78 (d, 1H), 7.68 (m, 1H), 7.45-7.41 (m, 4H), 6.34 (t,2H), 4.52-4.46 (m, 2H) 3.37-3.30 (m, 5H), 1.27 (t, 3H), 1.18 (s, 6H);LC-MS (ESI): Calculated mass: 519.62; Observed mass: 520.2 [M+H]⁺ (rt:1.17 min).

Example 114N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)acetamidea) N-(3-nitro-5-(1H-pyrazol-1-yl)phenyl)acetamide

To a solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (10g, 38.6 mmol) in DMF (100 ml) were added pyrazole (5.26 g, 77.2 mmol,2.0 eq.), copper(I) oxide (1.104 g, 7.72 mmol, 0.2 eq.) and cesiumcarbonate (25.15 g, 77.2 mmol, 2.0 eq.) and the mixture was heated at120° C. for 16 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off and the residue was purified bycolumn chromatography over silica gel (30% ethyl acetate in hexane) toafford the compound in 86% yield (8.2 g). ¹H NMR (300 MHz, DMSO-d₆): δ10.62 (s, 1H), 8.7 (d, 1H), 8.5-8.48 (m, 2H), 8.32 (t, 1H), 7.84 (d,1H), 6.62 (t, 1H), 2.08 (s, 3H); LC-MS (ESI): Calculated mass: 246.22;Observed mass: 247.1 [M+H]⁺ (rt: 0.6 min).

b) N-(3-amino-5-(1H-pyrazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 114(a) (8.2 g, 33.3 mmol) inethanol (70 ml) were added iron powder (3.72 g, 66.6 mmol, 2.0 eq.) and50% aqueous calcium chloride solution (15 ml). The mixture was stirredat 100° C. for 4 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off and the residue was purified bycolumn chromatography over silica gel to afford the compound in 99%yield (7.1 g). LC-MS (ESI): Calculated mass: 216.24; Observed mass: 217[M+H]⁺ (rt: 0.12 min).

c)N-(3-((4-bromo-2-nitrophenyl)amino)-5-(1H-pyrazol-1-yl)phenyl)acetamide

A solution of the compound of Example 114(b) (6.97 g, 32.23 mmol),4-bromo-1-fluoro-2-nitrobenzene (7.09 g, 32.23 mmol, 1.0 eq.) andpotassium fluoride (1.87 g, 32.23 mmol, 1.0 eq.) in DMF was heated at150° C. for 4 h. The mixture was quenched and extracted as in Example2(b). The solvent was distilled off to give the crude residue which waspurified by column chromatography over silica gel to give the compoundin 75% yield (10 g). LC-MS (ESI): Calculated mass: 416.23; Observedmass: 417 [M+H]⁺ (rt: 1.65 min).

d)N-(3-((2-amino-4-bromophenyl)amino)-5-(1H-pyrazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 114(c) (10 g, 24.03 mmol) inethanol (70 ml) were added iron powder (2.68 g, 48.05 mmol, 2.0 eq.) and50% aqueous calcium chloride solution (20 ml). The mixture was stirredat 100° C. for 4 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off and the residue was used withoutpurification in the next step.

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)acetamide

A mixture of the compound of Example 114(d) (crude from previous step)and formic acid (20 ml) was heated at 100° C. for 30 min. The formicacid was distilled off and the crude was dissolved in ethyl acetate. Theethyl acetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 84%yield (8.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (s, 1H), 8.57 (d, 1H),8.22 (m, 1H), 8.11 (s, 1H), 8.01 (d, 1H), 7.87-7.79 (m, 3H), 7.66 (d,1H), 7.51 (dd, 1H), 6.58 (t, 1H), 2.1 (s, 3H); LC-MS (ESI): Calculatedmass: 396.24; Observed mass: 397 [M+H]⁺ (rt: 1.38 min).

f) N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(l1H-pyrazol-1-yl)phenyl)acetamide

A solution of the compound of Example 114(e) (8.0 g, 20.19 mmol) in1,2-dimethoxyethane (100 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.3 g, 30.29 mmol, 1.5 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (4.67 g, 4.04 mmol, 0.2 eq.) and aqueous sodiumcarbonate (5.35 g, 50.5 mmol, 2.5 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby column chromatography over silica gel to afford the compound in 62%yield (5.0 g). ¹H NMR (300 MHz, CD₃OD): δ 9.21 (s, 1H), 8.35 (d, 1H),8.13-8.08 (m, 3H), 8.0 (s, 1H), 7.94 (s, 1H), 7.88-7.76 (m, 4H),6.73-6.69 (m, 1H), 3.98 (s, 3H), 2.23 (s, 3H), LC-MS (ESI): Calculatedmass: 397.43; Observed mass: 398.1 [M+H]⁺ (rt: 0.26 min).

Example 115N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrazol-1-yl)phenyl)methanesulfonamide a)3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)aniline

To a solution of the compound of Example 114 (4.0 g, 10.06 mmol) inethanol (25 ml) was added 20% aqueous solution of NaOH (5 ml) and thereaction was heated at 100° C. for 2 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe product in 78% yield (2.8 g).

b)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)methanesulfonamide

To a solution of the compound of Example 115(a) (50 mg, 0.14 mmol) inDCM was added pyridine (22 mg, 0.28 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (19 mg, 0.169 mmol, 1.2 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 20% yield (12 mg). ¹H NMR (300 MHz, CD₃OD):δ 8.68 (s, 1H), 8.35 (d, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H),7.84-7.81 (m, 1H), 7.77-7.73 (m, 2H), 7.71 (s, 1H), 7.67-7.63 (m, 1H),7.5-7.48 (m, 1H), 6.58-6.55 (m, 1H), 3.93 (s, 3H), 3.12 (s, 3H); LC-MS(ESI): Calculated mass: 433.49; Observed mass: 434.1 [M+H]⁺ (rt: 0.35min).

Example 116N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)propane-2-sulfonamide

The compound was prepared from the compound of Example 114 using theprocedures of Example 115. ¹H NMR (300 MHz, CD₃OD): δ 8.65 (s, 1H), 8.37(d, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.81 (m, 3H),7.76-7.74 (m, 1H), 7.69-7.67 (m, 1H), 7.55-7.54 (m, 1H), 6.61-6.6 (m,1H), 3.95 (s, 3H), 3.54-3.49 (m, 1H), 1.43 (d, 6H); LC-MS (ESI):Calculated mass: 461.54; Observed mass: 462.1 [M+H]⁺ (rt: 0.7 min).

Example 117N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 114 using theprocedures of Example 115 and cyclopropane sulfonyl chloride. ¹H NMR(300 MHz, CD₃OD): δ 8.54 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.93 (d,1H), 7.88 (s, 1H), 7.82-7.8 (m, 3H), 7.72 (d, 1H), 7.65-7.62 (m, 1H),7.53-7.52 (m, 1H), 6.6-6.59 (m, 1H), 3.95 (s, 3H), 2.81-2.78 (m, 1H),1.18-1.15 (m, 2H), 1.09-1.04 (m, 2H); LC-MS (ESI): Calculated mass:459.52; Observed mass: 460.1 [M+H]⁺ (rt: 0.58 min).

Example 118N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)benzenesulfonamide

The compound was prepared from the compound of Example 114 using theprocedures of Example 115. ¹H NMR (300 MHz, CD₃OD): δ 9.2 (s, 1H), 8.29(d, 1H), 8.12 (s, 1H), 8.0 (s, 1H), 7.96-7.93 (m, 3H), 7.83-7.75 (m,4H), 7.69-7.65 (m, 1H), 7.61-7.54 (m, 3H), 7.45 (t, 1H), 6.58 (m, 1H),3.98 (s, 3H); LC-MS (ESI): Calculated mass: 495.56; Observed mass: 496.2[M+H]⁺ (rt: 1.28 min).

Example 119N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)piperidine-1-sulfonamide

The compound was prepared from the compound of Example 114 using theprocedures of Example 115. ¹H NMR (300 MHz, CD₃OD): δ 8.92 (s, 1H), 8.3(d, 1H), 8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H),7.77-7.69 (m, 5H), 7.45 (m, 1H), 6.56 (m, 1H), 3.92 (s, 3H), 3.28-3.27(m, 4H), 1.6-1.49 (m, 6H); LC-MS (ESI): Calculated mass: 502.59;Observed mass: 503.1 [M+H]⁺ (rt: 0.1.33 min).

Example 1201-(furan-2-ylmethyl)-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)urea

To a solution of the compound of Example 115(a) (50 mg, 0.141 mmol) inDCM (1 ml) at 0° C. were added TEA (29 mg, 0.281 mmol, 2.0 eq.) and2-(isocyanatomethyl)furan (21 mg, 0.169 mmol, 1.2 eq.) and the mixturewas stirred at RT for 16 h. The solvent was removed under reducedpressure and the residue was purified by preparative HPLC to afford thecompound in 15% yield (10 mg). ¹H NMR (300 MHz, CD₃OD): δ 9.16 (s, 1H),8.35 (d, 1H), 8.1 (s, 1H), 8.0 (s, 1H), 7.95-7.94 (m, 2H), 7.91 (m, 1H),7.87 (d, 1H), 7.8-7.78 (m, 2H), 7.75-7.74 (m, 1H), 7.46 (d, 1H),6.6-6.59 (m, 1H), 6.38-6.37 (m, 1H), 6.31-6.3 (m, 1H), 4.43 (s, 2H),3.98 (s, 3H); LC-MS (ESI): Calculated mass: 478.51; Observed mass: 479.0[M+H]⁺ (rt: 0.72 min).

Example 1211-(4-fluorophenyl)-3-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)urea

The compound was prepared using the procedures of Example 120. ¹H NMR(300 MHz, CD₃OD): δ 9.7 (s, 1H), 9.3 (s, 1H), 8.67 (s, 1H), 8.62 (d,1H), 8.21 (s, 1H), 8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.83-7.81(m, 2H), 7.75-7.71 (m, 2H), 7.63-7.6 (m, 1H), 7.52-7.49 (m, 2H), 7.15(t, 2H), 6.61-6.6 (m, 1H), 3.88 (s, 3H); LC-MS (ESI): Calculated mass:492.51; Observed mass: 493.2 [M+H]⁺ (rt: 1.37 min).

Example 122N-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)-phenyl)acetamide

To a solution of the compound of Example 114(e) (200 mg, 0.505 mmol) inDMF (20 ml) were added pyrazole (41 mg, 0.606 mmol, 1.2 eq.), copper(I)oxide (0.7 mg, 0.0051 mmol, 0.01 eq.) and cesium carbonate (329 mg, 1.01mmol, 2.0 eq.) and the mixture was heated at 110° C. for 12 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by preparative HPLC to givethe product in 20% yield (37 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.9 (br s,1H), 8.37-8.33 (m, 2H), 8.19 (s, 1H), 8.13-8.12 (m, 1H), 8.06-8.05 (m,1H), 7.92 (m, 2H), 7.86-7.85 (m, 1H), 7.8-7.78 (m, 2H), 6.61-6.57 (m,2H), 2.22 (s, 3H); LC-MS (ESI): Calculated mass: 383.41; Observed mass:384.3 [M+H]⁺ (rt: 0.52 min).

Example 1231-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)-phenyl)-3-(furan-2-ylmethyl)ureaa)3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)aniline

To a solution of the compound of Example 122 (230 mg, 0.6 mmol) inethanol (20 ml) was added aqueous solution of sodium hydroxide (192 mg,4.8 mmol, 8.0 eq.) and the mixture was heated at 90° C. for 3 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 73% yield (150 mg).

b) 1-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrazol-1-yl)phenyl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 123(a) (50 mg, 0.146 mmol) inDCM was added TEA (45 mg, 0.439 mmol, 3.0 eq.) followed by2-(isocyanatomethyl)-furan (23 mg, 0.19 mmol, 1.3 eq.). The mixture wasstirred for 1 h and then quenched and extracted as of Example 1(d). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 8% yield (5 mg). ¹H NMR (300 MHz, CD₃OD): δ8.92 (br s, 1H), 8.34-8.31 (m, 2H), 8.16 (s, 1H), 7.92-7.89 (m, 4H),7.77 (m, 2H), 7.71 (m, 1H), 7.44 (m, 1H), 6.57 (m, 2H), 6.36-6.35 (m,1H), 6.29-6.28 (m, 1H), 4.41 (s, 2H); LC-MS (ESI): Calculated mass:464.48; Observed mass: 465.2 [M+H]⁺ (rt: 1.35 min).

Example 1241-(3-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)-phenyl)-3-cyclopentylurea

The compound was prepared from the compound of Example 122 using theprocedures of Example 123. ¹H NMR (300 MHz, CD₃OD): δ 9.21 (br s, 1H),8.35-8.33 (m, 2H), 8.22 (s, 1H), 7.98 (s, 2H), 7.93-7.88 (m, 2H),7.78-7.77 (m, 2H), 7.73-7.72 (m, 1H), 6.59-6.58 (m, 2H), 4.08 (m, 1H),1.99-1.96 (m, 2H), 1.75-1.71 (m, 2H), 1.68-1.33 (m, 2H), 1.52-1.49 (m,2H); LC-MS (ESI): Calculated mass: 452.51; Observed mass: 453.3 [M+H]⁺(rt: 1.42 min).

Example 125N-(3-(5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)-phenyl)acetamide

The compound was prepared from the compound of Example 114(e) using theprocedures of Example 122. ¹H NMR (300 MHz, CD₃OD): δ 9.43 (s, 1H), 8.77(s, 1H), 8.35 (d, 2H), 8.16 (m, 1H), 8.12 (s, 1H), 8.09-8.08 (m, 1H),8.03-8.02 (m, 1H), 8.0 (s, 1H), 7.98 (s, 1H), 7.83-7.82 (m, 1H),7.79-7.72 (m, 3H), 6.59-6.58 (m, 1H), 2.21 (s, 3H); LC-MS (ESI):Calculated mass: 383.41; Observed mass: 384.1 [M+H]⁺ (rt: 0.12 min).

Example 126N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)ethanesulfonamide

The compound was prepared from the compound of Example 114 using theprocedures of Example 115. ¹H NMR (400 MHz, CD₃OD): δ 9.13 (s, 1H), 8.36(d, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.88-7.78 (m, 5H),7.58 (s, 1H), 6.61-6.50 (m, 1H), 3.97 (s, 3H), 3.31 (quartet, 2H) 1.40(t, 3H); LC-MS (ESI): Calculated mass: 447.51; Observed mass: 448.1[M+H]⁺ (rt: 0.49 min).

Example 127N-(3-(5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)acetamide

A solution of the compound of Example 114(e) (0.5 g, 1.26 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min. Thecompound of Intermediate Example 9 (0.47 g, 1.89 mmol, 1.5 eq.) wasadded and the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.2g, 0.25 mmol, 0.2 eq.) and aqueous sodium carbonate (0.27 g, 2.52 mmol,2 eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by preparative HPLC to givethe product in 11% yield (60 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.52 (s,1H), 8.82-8.73 (m, 1H), 8.59 (d, 1H), 8.23-8.15 (m, 3H), 8.03-7.92 (m,2H), 7.83-7.74 (m, 2H), 7.72-7.59 (m, 2H), 6.59 (s, 1H), 4.23 (d, 2H),2.12 (s, 3H), 1.25-0.78 (m, 5H); LC-MS (ESI): Calculated mass: 437.50;Observed mass: 438.2 [M+H]⁺ (rt: 0.812 min).

Example 128N-(3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)acetamidea) tert-butyl4-(4-(1-(3-acetamido-5-(1H-pyrazol-1-yl)phenyl)-1H-benzo[d]-imidazol-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of the compound of Example 114(e) (0.6 g, 1.51 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min. Thecompound of Intermediate Example 5 (0.85 g, 2.27 mmol, 1.5 eq.) wasadded and the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.25g, 0.302 mmol, 0.2 eq.) and aqueous sodium carbonate (0.5 g, 4.53 mmol,3.0 eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by preparative HPLC to givethe product in 35% yield (0.3 g).

b)N-(3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 128(a) (300 mg, 0.53 mmol) inDCM (4 ml) at 0° C. was added trifluoroacetic acid (0.6 ml) and themixture was stirred at RT for 6 h. The solvent was distilled off and theresidue was purified by preparative HPLC to give the product in 89%yield (220 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.50 (s, 1H), 8.84 (s,1H), 8.73-8.63 (m, 1H), 8.61 (d, 1H), 8.52-8.38 (m, 1H), 8.35 (s, 1H),8.20 (s, 1H), 8.07 (d, 1H), 8.01 (s, 1H), 7.87-7.83 (m, 2H), 7.73-7.65(m, 2H), 6.62 (t, 1H), 4.36 (m, 1H), 3.50-3.35 (m, 2H), 3.17-3.10 (m,2H), 2.32-2.21 (m, 4H), 2.14 (s, 3H); LC-MS (ESI): Calculated mass:466.54; Observed mass: 467.2 [M+H]⁺ (rt: 0.128 min).

Example 129N-(3-(5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-5-(lH-pyrazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 128 (80 mg, 0.171 mmol) in DCM(10 ml) was added pyridine (27 mg, 0.34 mmol, 2 eq.) and methanesulfonylchloride (19 mg, 0.171 mmol, 1 eq.). The mixture was stirred for 4 h andquenched and and extracted as in Example 2(b). The solvent was distilledoff and the residue was purified by preparative HPLC to give the productin 19% yield (18 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 10.06(s, 1H), 8.58 (d, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.06-8.00 (m, 3H),7.89 (s, 1H), 7.83 (d, 1H), 7.78-7.74 (m, 2H), 6.62 (t, 1H), 4.36 (m,1H), 3.01-2.94 (m, 6H), 2.30 (s, 3H), 2.13 (s, 3H), 2.10-2.01 (m, 2H);LC-MS (ESI): Calculated mass: 544.63; Observed mass: 545.2 [M+H]⁺ (rt:0.40 min).

Example 130N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)-acetamidea)N-(3-(4-formyl-2-nitrophenylamino)-5-(1H-pyrazol-1-yl)phenyl)acetamide

A solution of the compound of Example 114(b) (0.35 g, 1.62 mmol),4-fluoro-3-nitrobenzaldehyde (0.24 g, 1.62 mmol, 1.0 eq.) and potassiumfluoride (94 mg, 1.62 mmol, 1.0 eq.) in DMF (2 ml) was heated at 130° C.for 4 h. The mixture was quenched and extracted as in Example 1(d). Thesolvent was distilled off and the residue was purified by columnchromatography (60-120 silica gel, 40% ethyl acetate in hexane) to givethe product in 51% yield (0.3 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.29 (s,1H), 10.03 (s, 1H), 9.87 (s, 1H), 8.71 (m, 1H), 8.43 (d, 1H), 8.05 (s,1H), 7.92 (d, 1H), 7.76 (s, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.27 (s,1H), 6.55 (s, 1H), 2.10 (s, 3H).

b)N-(3-(2-nitro-4-(oxazol-4-yl)phenylamino)-5-(1H-pyrazol-1-yl)phenyl)-acetamide

To a solution of the compound of Example 130(a) (0.3 g, 0.824 mmol) inmethanol (8 ml) was added potassium carbonate (0.18 g, 0.904 mmol, 1.1eq.) and the mixture was stirred for 10 min at RT. Toluenesulfonylmethylisocyanide (0.124 g, 0.904 mmol, 1.1 eq.) was added and the mixture wasrefluxed for 4 h. The solvent was distilled off and water was added tothe crude product. The mixture was extracted as in Example 1(d). Thesolvent was distilled off and the residue was purified by columnchromatography (60-120 silica gel, 40% ethyl acetate in hexane) to givethe product in 75% yield (0.25 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.23(s, 1H), 9.57 (s, 1H), 8.46-8.40 (m, 3H), 7.94-7.89 (m, 2H), 7.76-7.72(m, 2H), 7.57 (s, 1H), 7.49 (s, 1H), 7.42 (d, 1H), 6.55 (t, 1H), 2.01(s, 3H).

c)N-(3-(2-amino-4-(oxazol-4-yl)phenylamino)-5-(1H-pyrazol-1-yl)phenyl)-acetamide

To a solution of the compound of Example 130(b) (0.25 g, 0.62 mmol) inmethanol (15 ml) and ethyl acetate (7 ml) was added 10% Pd/C (30 mg) andthe reaction vessel was purged with nitrogen gas for 5 min. The mixturewas then hydrogenated with H₂ balloon for 4 h. The mixture was filteredthrough a pad of celite and the filtrate was concentrated to afford thecompound in 86% yield (0.2 g).

d)N-(3-(5-(oxazol-5-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-1-yl)phenyl)-acetamide

A mixture of the compound of Example 130(c) (0.2 g, 0.54 mmol) andformic acid (3 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and the residue was purified bypreparative HPLC to give the product in 6% yield (12 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.47 (s, 1H), 8.80 (br s, 1H), 8.60 (d, 1H), 8.46 (s,1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.94 (s, 1H), 7.86-7.81 (m, 3H),7.78-7.76 (m, 2H), 6.60 (t, 1H) 2.12 (s, 3H); LC-MS (ESI): Calculatedmass: 384.39; Observed mass: 385.1 [M+H]⁺ (rt: 0.39 min).

Example 131N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)acetamidea)N-(5-(5-bromo-3-nitropyridin-2-ylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide

A solution of the compound of Example 1(e) (1.07 g, 4.08 mmol),5-bromo-2-chloro-3-nitropyridine (0.97 g, 4.08 mmol, 1.0 eq.) andpotassium fluoride (0.24 g, 4.08 mmol, 1.0 eq.) in DMF (30 ml) washeated at 130° C. for 5 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off to afford the crude product(1.8 g).

b)N-(5-(3-amino-5-bromopyridin-2-ylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 131(a) (1.8 g, 3.8 mmol) in THF(30 ml) were added a solution of ammonium chloride (0.83 g, 15.5 mmol, 4eq.) in water (15 ml) and zinc (1.02 g, 15.5 mmol, 10 eq.). The mixturewas stirred at RT for 3 h and filtered. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe product in 97% yield (1.6 g).

c)N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluorobiphenyl-3-yl)-acetamide

A mixture of the compound of Example 131(b) (1.6 g, 3.7 mmol) and formicacid (15 ml) was heated at 90° C. for 1 h. Formic acid was thendistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 79%yield (1.3 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.0 (s, 1H),8.55 (s, 1H), 8.24 (s, 1H), 7.89 (d, 1H), 7.75-7.65 (m, 2H), 7.48-7.41(m, 2H), 7.27-7.26 (dt, 1H), 2.1 (s, 3H).

d)N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)acetamide

A solution of the compound of Example 131(c) (75 mg, 0.17 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42mg, 0.203 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (28 mg, 0.033 mmol, 0.2 eq.) and aqueoussodium carbonate (54 mg, 0.507 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 20% yield (15mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.94 (s, 1H), 8.71 (d,1H), 8.41 (d, 1H), 8.3 (s, 2H), 8.05 (s, 1H), 7.88 (s, 1H), 7.75-7.68(m, 2H), 7.48-7.42 (dt, 1H), 7.29-7.25 (dt, 1H), 3.89 (s, 3H), 2.1 (s,3H); LC-MS (ESI); Calculated mass: 444.15: Observed mass: 445.1 [M+H]⁺(rt: 1.39 min).

Example 132N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)methanesulfonamidea)2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-amine

To a solution of the compound of Example 131 (0.5 g, 1.1 mmol) inethanol (10 ml) was added aqueous solution of NaOH (392 mg, 9.79 mmol,8.9 eq.) and the mixture was heated at 85° C. for 2 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 79% yield (0.35 g).

b)N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 132(a) (70 mg, 0.174 mmol) inDCM (5 ml) was added pyridine (28 mg, 0.348 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (22 mg, 0.192 mmol, 1.1 eq.). The reaction wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 8% yield (7 mg). ¹H-NMR (300 MHz, CD₃OD): δ8.8 (br s, 1H), 8.7 (s, 1H), 8.32-8.28 (m, 1H), 8.12 (s, 1H), 7.95 (s,1H), 7.9-7.85 (m, 1H), 7.8-7.77 (s, 1H), 7.7-7.6 (m, 1H), 7.53-7.49 (m,2H), 7.18-7.05 (m, 2H), 3.96 (s, 3H), 3.13 (s, 3H); LC-MS (ESI):Calculated mass: 480.12; Observed mass: 481.3 [M+H]⁺ (rt: 1.38 min).

Example 133N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 131 using theprocedures of Example 132. ¹H NMR (300 MHz, DMSO-d₆): δ 8.8 (s, 1H), 8.7(d, 1H), 8.29 (d, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.86 (t, 1H),7.8-7.77 (m, 1H), 7.7-7.49 (m, 4H), 7.05-7.18 (m, 1H), 3.96 (s, 3H),3.29 (quartet, 2H), 1.37 (t, 3H); LC-MS (ESI): Calculated mass: 494.13;Observed mass: 495.1 [M+H]⁺ (rt: 1.46 min).

Example 134N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)benzenesulfonamide

The compound was prepared from the compound of Example 131 using theprocedures of Example 132. LC-MS (ESI): Calculated mass: 542.13;Observed mass: 543.1 [M+H]⁺ (rt: 1.64 min).

Example 135N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 131(c) using theprocedures of Example 131(d). ¹H-NMR (300 MHz, DMSO-d₆): δ 10.43 (s,1H), 8.92 (s, 1H), 8.73-8.74 (d, 1H), 8.44-8.40 (m, 1H), 8.30-8.25 (m,1H), 8.05 (s, 1H), 7.25-7.9 (m, 6H), 3.59-3.50 (m, 1H), 2.11 (s, 3H),2.02-1.93 (m, 2H), 1.88-1.83 (m, 4H), 1.71-1.66 (m, 2H); LC-MS (ESI):Calculated mass: 498.20; Observed mass: 499.2 [M+H]⁺ (rt: 1.63 min).

Example 136N-(2′,4′-difluoro-5-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]-pyridin-3-yl)biphenyl-3-yl)acetamidea) tert-butyl4-(4-(3-(5-acetamido-2′,4′-difluorobiphenyl-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A solution of the compound of Example 131(c) (150 mg, 0.338 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min.tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(153 mg, 0.406 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (55 mg, 0.068 mmol, 0.2 eq.) and aqueous sodiumcarbonate (107 mg, 1.01 mmol, 3.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was obtainedin 48% yield (100 mg).

b)N-(2′,4′-difluoro-5-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)biphenyl-3-yl)acetamide

To a solution of the compound of Example 136(a) (100 mg, 0.16 mmol) in1,4-dioxane (5 ml) at 0° C. was added HCl in dioxane and stirred at RTfor 2 h. The solvent was distilled off and the residue was purified bypreparative HPLC to give the product in 30% yield (25 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.2 (s, 1H), 8.95-8.91 (m, 1H), 8.78-8.75 (m, 2H),8.48-8.30 (m, 3H), 8.15-8.10 (m, 1H), 7.84-7.64 (m, 3H), 7.48-7.38 (m,1H), 7.30-7.20 (m, 1H), 4.6-4.45 (m, 1H), 3.2-3.0 (m, 4H), 2.3-2.05 (m,7H); LC-MS (ESI): Calculated mass: 513.21; Observed mass: 514.2 [M+H]⁺(rt: 0.21 min).

Example 137N-(5-(6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 131(c) (1.5 g, 3.3 mmol) in DMF(20 ml) were added pyrazole (0.22 g, 3.3 mmol, 1 eq.), copper(I) oxide(0.243 g, 1.69 mmol, 0.5 eq.) and cesium carbonate (1.73 g, 5.3 mmol,1.6 eq.) and then heated at 90° C. for 12 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (60-120 silica gel, 70%ethyl acetate in hexane) to give the product in 35% yield (0.5 g). ¹HNMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 9.05-8.97 (m, 2H), 8.68-8.60 (m,2H), 8.32-825 (br s, 1H), 7.92-7.8 (m, 2H), 7.75-7.65 (m, 2H), 7.48-7.38(m, 1H), 7.30-7.20 (m, 1H), 6.63-6.60 (m, 1H), 2.1 (s, 3H); LC-MS (ESI):Calculated mass: 430.14; Observed mass: 431.1 [M+H]⁺ (rt: 1.46 min).

Example 138N-(2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamidea) N-(2′,5′-difluoro-5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (0.8 g,3.07 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N₂ bubblingfor 5 min. 2,5-Difluorophenylboronic acid (0.58 g, 3.69 mmol, 1.2 eq.)was added and the mixture was degassed for another 5 min. Pd(dppf)Cl₂(0.5 g, 0.615 mmol, 0.2 eq.) and aqueous sodium carbonate (0.98 g, 9.23mmol, 3.0 eq.) were added and the procedure of Example 1(d) wasfollowed. The crude residue of the product was purified by columnchromatography (60-120 silica gel, 25% ethyl acetate in hexane) to givethe product in 67% yield (0.6 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.56 (s,1H), 8.65 (t, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.56-7.52 (m, 1H),7.47-7.37 (m, 2H), 2.12 (s, 3H).

b) N-(5-amino-2′,5′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 138(a) (0.6 g, 2.05 mmol) inmethanol (10 ml) and ethyl acetate (3 ml) was added 10% Pd/C (100 mg)and the reaction vessel was purged with nitrogen gas for 5 min. Themixture was then hydrogenated with H₂ balloon for a period of 12 h. Themixture was filtered through a pad of celite and the filtrate wasconcentrated to afford the compound in 93% yield (0.5 g).

c)N-(5-(4-bromo-2-nitrophenylamino)-2′,5′-difluorobiphenyl-3-yl)acetamide

A solution of the compound of Example 138(b) (0.5 g, 1.9 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.42 g, 1.9 mmol, 1.0 eq.) andpotassium fluoride (0.11 g, 1.9 mmol, 1.0 eq.) in DMF (2 ml) was heatedat 130° C. for 5 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off and the residue was purified bycolumn chromatography (60-120 silica gel, 30% ethyl acetate in hexane)to give the product in 57% yield (0.5 g).

d)N-(5-(2-amino-4-bromophenylamino)-2′,5′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 138(c) (0.5 g, 1.08 mmol) inTHF (10 ml) were added a solution of ammonium chloride (0.46 g, 8.67mmol, 8 eq.) in water (2 ml) and zinc (0.57 g, 8.67 mmol, 8 eq.). Themixture was stirred at 45° C. for 2 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 86% yield (0.4 g).

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,5′-difluorobiphenyl-3-yl)acetamide

A mixture of the compound of Example 138(d) (0.4 g, 0.93 mmol) andformic acid (4 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 85%yield (0.35 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.75 (s,1H), 8.04 (d, 2H), 7.86 (s, 1H), 7.69 (d, 1H), 7.64-7.56 (m, 3H),7.54-7.38 (m, 1H), 7.37-7.31 (m, 1H), 2.12 (s, 3H).

f)N-(2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

A solution of the compound of Example 138(e) (100 mg, 0.226 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (57mg, 0.27 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (37 mg, 0.045 mmol, 0.2 eq.) and aqueoussodium carbonate (71 mg, 0.678 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 20% yield (20mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.64 (s, 1H), 8.20 (s,1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.8-7.68 (m, 2H),7.6-7.45 (m, 4H), 7.27 (t, 1H), 3.88 (s, 3H), 2.12 (s, 3H); LC-MS (ESI):Calculated mass: 443.45; Observed mass: 444.1 [M+H]⁺ (rt: 1.147 min).

Example 139N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)acetamide

A solution of the compound of Example 138(e) (5 g, 11.34 mmol) in1,2-dimethoxyethane (100 ml) was degassed by N₂ bubbling for 5 min.4-(2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine(4.2 g, 13.61 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (1.3 g, 1.13 mmol, 0.1 eq.) and aqueous sodiumcarbonate (2.4 g, 22.67 mmol, 2.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby preparative HPLC to give the product in 37% yield (2.3 g). ¹H NMR(400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.87 (s, 1H), 8.34 (s, 1H), 8.17(s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.80-7.53 (m, 2H), 7.66-7.58 (m,3H), 7.46-7.44 (m, 1H), 7.38-7.32 (m, 1H), 4.59 (t, 2H), 3.76-3.67 (m,4H), 3.43-3.39 (m, 2H), 2.54-2.44 (m, 4H), 2.07 (s, 3H); LC-MS (ESI):Calculated mass: 542.58; Observed mass: 543.3 [M+H]⁺ (rt: 0.22 min).

Example 140N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)methanesulfonamidea)2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-amine

To a solution of the compound of Example 139 (2.2 g, 4.0 mmol) inethanol (100 ml) was added aqueous solution of NaOH (2.0 g, 50 mmol,12.5 eq.) and the mixture was heated at 100° C. for 4 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 90% yield (1.8 g).

b)N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)methanesulfonamide

To a solution of the compound of Example 140(a) (100 mg, 0.2 mmol) inDCM (2 ml) was added pyridine (32 mg, 0.4 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (30 mg, 0.26 mmol, 1.3 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 26% yield (30 mg). ¹H NMR (400 MHz, CD₃OD):δ 9.34 (s, 1H), 8.25 (s, 1H), 8.06-8.05 (m, 2H), 7.86. 7.80 (s, 2H),7.74-7.73 (m, 1H), 7.68 (m, 1H), 7.60-7.59 (m, 1H), 7.44-7.39 (m, 1H),7.33-7.27 (m, 1H), 7.24-7.19 (m, 1H), 4.69 (t, 2H), 3.94-3.88 (m, 4H),3.76 (t, 2H), 3.54-3.40 (m, 4H), 3.19 (s, 3H); LC-MS (ESI): Calculatedmass: 578.63; Observed mass: 579.3 [M+H]⁺ (rt: 0.26 min).

Example 141N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 139 using theprocedures of Example 140. ¹H NMR (400 MHz, DMSO-d₆): δ 10.34 (s, 1H),8.69 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.72-7.61 (m,5H), 7.51-7.44 (m, 2H), 7.39-7.35 (m, 1H), 4.27 (t, 2H), 3.58 (t, 4H),3.32-3.28 (m, 2H), 2.77 (t, 2H), 2.45 (m, 4H), 1.22 (t, 3H); LC-MS(ESI): Calculated mass: 592.66; Observed mass: 593.2 [M+H]⁺ (rt: 0.332min).

Example 142N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)propane-2-sulfonamide

The compound was prepared from the compound of Example 139 using theprocedures of Example 140. ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H),8.79 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.74-7.62 (m,5H), 7.54 (s, 1H), 7.51-7.45 (m, 1H), 7.41-7.35 (m, 1H), 4.61 (t, 2H),3.70-3.63 (m, 6H), 3.52-3.42 (m, 3H), 3.40-3.28 (m, 2H), 1.43 (d, 6H);LC-MS (ESI): Calculated mass: 606.69; Observed mass: 607.4 [M+H]⁺ (rt:0.55 min).

Example 143N-(2′,5′-difluoro-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)biphenyl-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 139 using theprocedures of Example 140 and cyclopropane sulfonyl chloride. ¹H NMR(400 MHz, DMSO-d₆): δ 10.31 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.14(s, 1H), 8.07 (s, 1H), 7.73 (d, 1H), 7.67-7.63 (m, 4H), 7.55 (s, 1H),7.50-7.45 (m, 2H), 4.60 (t, 2H), 3.99-3.79 (m, 2H), 3.69-3.63 (m, 6H),3.20-3.17 (m, 2H), 2.91-2.88 (m, 1H), 1.1-1.0 (d, 4H); LC-MS (ESI):Calculated mass: 604.67; Observed mass: 605.4 [M+H]⁺ (rt: 0.48 min).

Example 144N-(5-(5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,5′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 138(e) using theprocedures of Example 139. ¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H),8.74 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H),7.79-7.73 (m, 2H), 7.64-7.57 (m, 3H), 7.45-7.42 (m, 1H), 7.36-7.34 (m,1H), 4.56 (t, 2H), 3.62 (t, 2H), 3.84 (s, 6H), 2.12 (s, 3H); LC-MS(ESI): Calculated mass: 500.54; Observed mass: 501.2 [M+H]⁺ (rt: 0.22min).

Example 145N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,5′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 138(e) (2.5 g, 5.67 mmol, 1eq.) in DMF (10 ml) were added pyrazole (0.77 g, 11.3 mmol, 2 eq.),copper(I) oxide (1.62 g, 11.3 mmol, 2.0 eq.) and cesium carbonate (3.67g, 11.3 mmol, 2.0 eq.) and the mixture was heated at 90° C. for 48 h Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by preparative HPLC to givethe product in 79% yield (1.92 g). ¹H NMR (400 MHz, CD₃OD): δ 10.43 (s,1H), 8.84 (s, 1H), 8.60 (d, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.97-7.82(m, 3H), 7.76 (s, 1H), 7.63-7.60 (m, 2H), 7.49-7.32 (m, 1H), 6.56 (s,1H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 429.42; Observed mass:430.2 [M+H]⁺ (rt: 1.45 min).

Example 146N-(5-(5-(1H-pyrrol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,5′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 138(e) (250 mg, 0.57 mmol, 1eq.) in DMF (1 ml) were added pyrazole (77 mg, 1.13 mmol, 2 eq.),copper(I) oxide (162 mg, 1.13 mmol, 2.0 eq.) and cesium carbonate (367mg, 1.13 mmol, 2.0 eq.) and the mixture was heated at 90° C. for 48 h.The mixture was quenched and extracted as in Example 1(d). The solventwas distilled off and the residue was purified by preparative HPLC togive the product in 45% yield (110 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.45 (s, 1H), 8.81 (s, 1H), 8.15 (s, 1H), 8.00 (d, 1H), 7.86-7.80 (m,2H), 7.66-7.62 (m, 3H), 7.46-7.44 (m, 4H), 6.29 (t, 2H), 2.13 (s, 3H);LC-MS (ESI): Calculated mass: 428.43; Observed mass: 429.1 [M+H]⁺ (rt:1.647 min).

Example 147N-(3-(benzofuran-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamidea) N-(3-(benzofuran-2-yl)-5-nitrophenyl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (2 g,7.7 mmol) in 1,2-dimethoxyethane (25 ml) was degassed by N₂ bubbling for5 min. 2-(Benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.45g, 10 mmol, 1.3 eq.) was added and the mixture was degassed for another5 min. Pd(dppf)Cl₂ (0.63 g, 0.77 mmol, 0.1 eq.) and aqueous sodiumcarbonate (2.45 g, 23.1 mmol, 3.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was directlyused for the next step.

b) N-(3-amino-5-(benzofuran-2-yl)phenyl)acetamide

To a solution of the compound of Example 147(a) (1.8 g, 6.08 mmol) inethanol (30 ml) were added calcium chloride (1.35 g, 12.16 mmol, 2 eq.)and iron powder (0.7 g, 12.16 mmol, 2 eq.) and the mixture was heated at100° C. for 2 h and filtered. The filtrate was diluted with water andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (100-200 neutral alumina,4% methanol in chloroform) to give the product in 90% yield (1.45 g).

c) N-(3-(benzofuran-2-yl)-5-(4-bromo-2-nitrophenylamino)phenyl)acetamide

A solution of the compound of Example 147(b) (1.45 g, 5.45 mmol),4-bromo-1-fluoro-2-nitrobenzene (1.2 g, 5.45 mmol, 1.0 eq.) andpotassium fluoride (0.32 g, 5.45 mmol, 1.0 eq.) in DMF (5 ml) was heatedat 100° C. for 12 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 40% ethyl acetate inhexane) to give the product in 59% yield (1.5 g).

d) N-(3-(2-amino-4-bromophenylamino)-5-(benzofuran-2-yl)phenyl)acetamide

To a solution of the compound of Example 147(c) (1.45 g, 3.12 mmol) inethanol (35 ml) were added calcium chloride (0.69 g, 6.24 mmol, 2 eq.)and iron powder (0.36 g, 6.24 mmol, 2 eq.) and the mixture was heated at100° C. for 2 h and filtered. The filtrate was diluted with water andextracted as in Example 1(d). The solvent was distilled off and theresidue was directly used for the next step.

e)N-(3-(benzofuran-2-yl)-5-(5-bromo-1H-benzo[d]imidazol-1-yl)phenyl)acetamide

A mixture of the compound of Example 147(d) (1.36 g, 3.2 mmol) andformic acid (2 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 61%yield (0.85 g).

f)N-(3-(benzofuran-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamide

A solution of the compound of Example 147(e) (0.8 g, 1.8 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.56 g, 2.7 mmol, 1.5 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (0.207 g, 0.18 mmol, 0.1 eq.) and aqueoussodium carbonate (3.8 g, 3.6 mmol, 2.0 eq.) were added and the procedureof Example 1(d) was followed. The crude residue of the product waspurified by preparative HPLC to give the pure product in 75% yield (0.6g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.46 (s, 1H), 8.78 (s, 1H), 8.21 (m,2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.96 (s, 2H), 7.74-7.64 (m, 3H),7.63-7.59 (m, 2H), 7.34-7.31 (m, 2H), 3.89 (s, 3H), 2.15 (s, 3H); LC-MS(ESI): Calculated mass: 447.49; Observed mass: 448.1 [M+H]⁺ (rt: 1.397min).

Example 148N-(5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-acetamidea) N-(5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (1 g,3.87 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N₂ bubblingfor 5 min. Phenyl-boronic acid (0.61 g, 5.04 mmol, 1.3 eq.) was addedand the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.63 g,0.77 mmol, 0.2 eq.) and aqueous sodium carbonate (1.23 g, 11.6 mmol, 3.0eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by column chromatography(60-120 silica gel, 50% ethyl acetate in hexane) to give the product in61% yield (0.6 g).

b) N-(5-aminobiphenyl-3-yl)acetamide

To a solution of N-(5-nitrobiphenyl-3-yl)acetamide (1.2 g, 4.68 mmol) inTHF (10 ml) were added a solution of ammonium chloride (2 g, 37.4 mmol,8 eq.) in water (2 ml) and zinc (2.36 g, 37.4 mmol, 8 eq.). The mixturewas stirred at 45° C. for 2 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 94% yield (1 g).

c) N-(5-(4-bromo-2-nitrophenylamino)biphenyl-3-yl)acetamide

A solution of N-(5-aminobiphenyl-3-yl)acetamide (1 g, 4.54 mmol),4-bromo-1-fluoro-2-nitrobenzene (1.03 g, 4.54 mmol, 1.0 eq.) andpotassium fluoride (0.26 g, 4.54 mmol, 1.0 eq.) in DMF (5 ml) was heatedat 100° C. for 12 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 50% ethyl acetate inhexane) to give the product in 52% yield (1 g).

d) N-(5-(2-amino-4-bromophenylamino)biphenyl-3-yl)acetamide

To a solution of the compound of Example 148(c) (1.0 g, 2.35 mmol) inTHF (10 ml) were added a solution of ammonium chloride (1.18 g, 18.8mmol, 8 eq.) in water (2 ml) and zinc (1 g, 18.8 mmol, 8 eq.). Themixture was stirred at 45° C. for 2 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 43% yield (0.4 g).

e) N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

A mixture of the compound of Example 148(d) (0.4 g, 1.01 mmol) andformic acid (10 ml) was heated at 100° C. for 2 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and the residue was purified bycolumn chromatography (60-120 silica gel, 50% ethyl acetate in hexane)to give the product in 85% yield (0.35 g).

f)N-(5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)-acetamide

A solution of the compound of Example 148(e) (400 mg, 0.99 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(220 mg, 1.05 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (230 mg, 0.197 mmol, 0.2 eq.) and aqueoussodium carbonate (320 mg, 3.01 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 12% yield (50mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.36 (s, 1H), 8.68 (s, 1H), 8.18 (s,1H), 8.02-7.97 (m, 2H), 7.93-7.88 (m, 2H), 7.75-7.67 (s, 3H), 7.61-7.49(m, 4H), 7.43 (t, 1H), 3.87 (s, 3H), 2.12 (s, 3H); LC-MS (ESI):Calculated mass: 407.47; Observed mass: 408.1 [M+H]⁺ (rt: 1.67 min).

Example 149N-(4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamidea) N-(4′-methoxy-5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (1 g,3.8 mmol) in 1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for5 min. 4-Methoxyphenylboronic acid (0.69 g, 4.4 mmol, 1.1 eq.) was addedand the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.31 g,0.38 mmol, 0.1 eq.) and aqueous sodium carbonate (1 g, 9.5 mmol, 2.5eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by column chromatography(60-120 silica gel, 40% ethyl acetate in hexane) to give the product in73% yield (0.8 g).

b) N-(5-amino-4′-methoxybiphenyl-3-yl)acetamide

To a solution of N-(4′-methoxy-5-nitrobiphenyl-3-yl)acetamide (4 g,13.98 mmol) in ethanol (50 ml) were added calcium chloride (3.1 g, 27.96mmol, 2 eq.) and iron powder (1.45 g, 27.96 mmol, 2 eq.) and the mixturewas heated at 100° C. for 2 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 87% yield (3.1 g).

c) N-(5-(4-bromo-2-nitrophenylamino)-4′-methoxybiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 149(b) (3.1 g,12.11 mmol) using the procedure of Example 148(c) to give the titleproduct in 52% yield (2.9 g).

d) N-(5-(2-amino-4-bromophenylamino)-4′-methoxybiphenyl-3-yl)acetamide

To a solution of the compound of Example 149(c) (2.9 g, 6.37 mmol) inethanol (30 ml) were added calcium chloride (1.4 g, 12.74 mmol, 2 eq.)and iron powder (0.66 g, 12.74 mmol, 2 eq.) and the mixture was heatedat 100° C. for 2 h and filtered. The filtrate was diluted with water andextracted as described in Example 1(d). The solvent was distilled off toafford the crude residue which was directly used for the next step.

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-4′-methoxybiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 149(d) (2.7 g,6.37 mmol) using the procedure of Example 148(e) to give the product in79% yield (2.2 g).

f)N-(4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 149(e) using theprocedure of Example 148(f) to give the product in 67% yield (0.54 g).¹H NMR (300 MHz, DMSO-d₆): δ 8.48 (s, 1H), 7.96-7.84 (m, 4H), 7.74-7.45(m, 7H), 7.01 (d, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 2.19 (s, 3H); LC-MS(ESI): Calculated mass: 437.49; Observed mass: 437.9 [M+H]⁺ (rt: 0.89min).

Example 150N-(3′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)biphenyl-3-yl)acetamidea) N-(3′,4′-difluoro-5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (0.7 g,2.69 mmol) in 1,2-dimethoxyethane (15 ml) was degassed by N₂ bubblingfor 5 min. 3,4-Difluorophenylboronic acid (0.5 g, 3.23 mmol, 1.2 eq.)was added and the mixture was degassed for another 5 min. Pd(dppf)Cl₂(0.44 g, 0.54 mmol, 0.2 eq.) and aqueous sodium carbonate (0.86 g, 8.07mmol, 3.0 eq.) were added and the procedure of Example 1(d) wasfollowed. The crude residue of the product was purified by columnchromatography (60-120 silica gel, 25% ethyl acetate in hexane) to givethe product in 76% yield (0.6 g).

b) N-(5-amino-3′,4′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 150(a) (0.6 g, 2.05 mmol) inmethanol (10 ml) and ethyl acetate (2 ml) was added 10% Pd/C (100 mg)and the reaction vessel was purged with nitrogen gas for 5 min. Themixture was then hydrogenated with H₂ balloon for 12 h. The mixture wasfiltered through a pad of celite and the filtrate was concentrated underreduced pressure to afford the compound in 93% yield (0.5 g).

c)N-(5-(4-bromo-2-nitrophenylamino)-3′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 150(b) (3.1 g,12.11 mmol) using the procedure of Example 148(c) to give the product in57% yield (0.5 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.16 (s, 1H), 9.43 (s,1H), 8.23 (d, 1H), 7.69-7.58 (m, 3H), 7.41-7.38 (m, 2H), 7.29-7.26 (m,2H), 7.19 (s, 1H), 2.04 (s, 3H).

d)N-(5-(2-amino-4-bromophenylamino)-3′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 150(c) (0.5 g,1.08 mmol) using the procedure of Example 148(d) to give the product in86% yield (0.4 g).

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-3′,4′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 150(d) (0.4 g,0.93 mmol) using the procedure of Example 148(e) to give the product in97% yield (0.4 g).

f)N-(3′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 150(e) (0.1 g,0.226 mmol) using the procedure of Example 148(f) to give the product in30% yield (30 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.03 (s,1H), 8.24 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.90-7.85(s, 2H), 7.76-7.74 (m, 1H), 7.71 (s, 1H), 7.68-7.66 (m, 1H), 7.61-7.59(m, 2H), 3.88 (s, 3H), 2.13 (s, 3H); LC-MS (ESI): Calculated mass:443.45; Observed mass: 444.1 [M+H]⁺ (rt: 1.3 min).

Example 151N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamidea) N-(2′,6′-difluoro-5-nitrobiphenyl-3-yl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (20 g,77 mmol) in 1,2-dimethoxyethane (250 ml) was degassed by N₂ bubbling for5 min. 2,6-Difluorophenylboronic acid (14.6 g, 92.4 mmol, 1.2 eq.) wasadded and the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (6.28g, 7.7 mmol, 0.1 eq.) and aqueous sodium carbonate (24.49 g, 231 mmol,3.0 eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by column chromatography(60-120 silica gel, 30% ethyl acetate in hexane) to give the product in94% yield (21.2 g). LC-MS (ESI): Calculated mass: 292.24; Observed mass:293.1 [M+H]⁺ (rt: 1.49 min).

b) N-(5-amino-2′,6′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 151(a) (21 g, 72mmol) using the procedure of Example 148(b) to give the product in 95%yield (18 g).

c)N-(5-(4-bromo-2-nitrophenylamino)-2′,6′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 151(b) (8 g, 30.5mmol) using the procedure of Example 148(c) to give the product in 96%yield (13.5 g).

d)N-(5-(2-amino-4-bromophenylamino)-2′,6′-difluorobiphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 151(c) (13.5 g,29.22 mmol) using the procedure of Example 148(d) to give the product in95% yield (12 g).

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,6′-difluorobiphenyl-3-yl)-acetamide

The compound was prepared from the compound of Example 151(d) (12 g,27.84 mmol) using the procedure of Example 148(e) to give the product in96% yield (11.8 g).

f)N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)acetamide

The compound was prepared from the compound of Example 151(e) (2.5 g,5.67 mmol) using the procedure of Example 148(f) to give the product in84% yield (2.1 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.56 (s,1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.71-7.47(m, 5H), 7.27 (t, 2H), 3.85 (s, 3H), 2.09 (s, 3H); LC-MS (ESI):Calculated mass: 443.45; Observed mass: 444.0 [M+H]⁺ (rt: 1.34 min).

Example 152N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,6′-difluorobiphenyl-3-yl)acetamide

To a solution of the compound of Example 151(e) (2.5 g, 5.67 mmol) inDMF (20 ml) were added pyrazole (0.96 g, 14.18 mmol, 2.5 eq.), copper(I)oxide (0.81 g, 5.67 mmol, 1 eq.) and cesium carbonate (4.6 g, 14.18mmol, 2.5 eq.) and the mixture was heated at 90° C. for 48 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by preparative HPLC to givethe product in 91% yield (2.2 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s,1H), 8.67 (s, 1H), 8.57 (d, 1H), 8.20 (d, 1H), 8.06 (s, 1H), 7.92-7.88(m, 1H), 7.77-7.74 (m, 3H), 7.53-7.49 (m, 2H), 7.30-7.25 (m, 2H), 6.54(t, 1H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 429.42; Observedmass: 430.1 [M+H]⁺ (rt: 1.50 min). Example 153.

N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamidea) N-(3-(1-methyl-1H-pyrazol-4-yl)-5-nitrophenyl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide (0.5 g, 1.9 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.513 g, 2.47 mmol, 1.3 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (0.155 g, 0.19 mmol, 0.1 eq.) and aqueoussodium carbonate (0.5 g, 4.75 mmol, 2.5 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by column chromatography (60-120 silica gel, 30% ethylacetate in hexane) to give the product in 81% yield (0.4 g).

b) N-(3-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide

To a solution of the compound of Example 153(a) (0.4 g, 1.54 mmol) inethanol (25 ml) were added calcium chloride (0.34 g, 3.08 mmol, 2 eq.)and iron powder (0.16 g, 3.08 mmol, 2 eq.) and the mixture was heated at100° C. for 2 h and filtered. The filtrate was diluted with water andextracted as in Example 1(d). The solvent was distilled off to affordthe product in 85% yield (0.3 g). LC-MS (ESI): Calculated mass: 230.27;Observed mass: 231.1 [M+H]⁺ (rt: 0.225 min).

c)N-(3-(4-bromo-2-nitrophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-acetamide

A solution of the compound of Example 153(b) (0.3 g, 1.3 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.29 g, 1.3 mmol, 1.0 eq.) andpotassium fluoride (0.075 g, 1.3 mmol, 1.0 eq.) in DMF (5 ml) was heatedat 100° C. for 12 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was directlyused for the next step.

d)N-(3-(2-amino-4-bromophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-acetamide

To a solution of the compound of Example 153(c) (0.6 g, 1.3 mmol) inethanol (20 ml) were added calcium chloride (0.29 g, 2.6 mmol, 2 eq.)and iron powder (0.14 g, 2.6 mmol, 2 eq.) and the mixture was heated at100° C. for 2 h and filtered. The filtrate was diluted with water andextracted as in Example 1(d). The solvent was distilled off and theresidue was directly used for the next step.

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)-phenyl)acetamide

A mixture of the compound of Example 153(d) (0.52 g, 1.3 mmol) andformic acid (2 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 54%yield (0.28 g). LC-MS (ESI): Calculated mass: 410.27; Observed mass:411.0 [M+H]⁺ (rt: 0.84 min).

f)N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide

A solution of the compound of Example 153(e) (0.15 g, 0.365 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.091 g, 0.439 mmol, 1.2 eq.) was added and the mixture was degassedfor another 5 min. Pd(PPh₃)₄ (0.043 g, 0.037 mmol, 0.1 eq.) and aqueoussodium carbonate (0.077 g, 0.73 mmol, 2.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 12% yield (18mg). ¹H NMR (300 MHz, CD₃OD): δ 9.39 (s, 1H), 8.10-7.91 (m, 6H),7.80-7.77 (m, 3H), 7.63 (s, 1H), 3.96 (s, 6H), 2.20 (s, 3H); LC-MS(ESI): Calculated mass: 443.45; Observed mass: 411.46 [M+H]⁺ (rt: 0.28min).

Example 154N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)phenyl)acetamidea) N-(3-nitro-5-(2-oxopyridin-1 (2H)-yl)phenyl)acetamide

To a solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.85 mmol),pyridin-2-ol (0.4 g, 4.24 mmol, 1.1 eq.), potassium carbonate (1 g, 1.3mmol, 1.0 eq.) and copper(I) iodide (10 mg) in toluene (20 ml) was addedtrans cyclohexyl diamine (5 mg, 0.039 mmol, 0.01 eq.) and the mixturewas heated at 100° C. for 16 h. The mixture was quenched and extractedas in Example 1(d). The solvent was distilled off and the residue waspurified by column chromatography (60-120 silica gel, 50% ethyl acetatein hexane) to give the product in 95% yield (1 g).

b) N-(3-amino-5-(2-oxopyridin-1 (2H)-yl)phenyl)acetamide

To a solution of the compound of Example 154(a) (1.2 g, 4.4 mmol) inethanol (20 ml) and water (2 ml) were added calcium chloride (0.98 g,8.8 mmol, 2 eq.) and iron powder (0.46 g, 8.8 mmol, 2 eq.) and themixture was heated at 100° C. for 4 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 89% yield (0.95 g). LC-MS (ESI):Calculated mass: 243.26; Observed mass: 244.1 [M+H]⁺ (rt: 0.19 min)

c)N-(3-(4-bromo-2-nitrophenylamino)-5-(2-oxopyridin-1(2H)-yl)phenyl)-acetamide

A solution of the compound of Example 154(b) (0.95 g, 3.9 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.86 g, 3.9 mmol, 1.0 eq.) andpotassium fluoride (0.23 g, 3.9 mmol, 1.0 eq.) in DMF (1 ml) was heatedat 150° C. for 2 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off and the residue was purified bycolumn chromatography (100-200 silica gel, 1% methanol in DCM) to givethe product in 69% yield (1.2 g).

d) N-(3-(2-amino-4-bromophenylamino)-5-(2-oxopyridin-1(2H)-yl)phenyl)acetamide

To a solution of the compound of Example 154(c) (1.2 g, 2.7 mmol) inethanol (20 ml) were added calcium chloride (0.6 g, 5.4 mmol, 2 eq.) andiron powder (0.28 g, 5.4 mmol, 2 eq.) and the mixture was heated at 100°C. for 4 h and filtered. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the crude residue wasdirectly used for the next step.

e) N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)phenyl)-acetamide

A mixture of the compound of Example 154(d) (1.12 g, 2.7 mmol) andformic acid (1 ml) was heated at 100° C. for 2 h. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 61%yield (0.7 g). LC-MS (ESI): Calculated mass: 423.26; Observed mass:424.9 [M+H]⁺ (rt: 1.065 min).

f)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)phenyl)acetamide

A solution of the compound of Example 154(e) (0.7 g, 1.65 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.41 g, 1.98 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (0.19 g, 0.165 mmol, 0.1 eq.) and aqueoussodium carbonate (0.35 g, 3.3 mmol, 2.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 64% yield (0.45g). ¹H NMR (300 MHz, CD₃OD-d₆): δ 9.35 (s, 1H), 8.29-8.28 (m, 1H), 8.11(s, 1H), 8.00 (s, 1H), 7.94 (d, 1H), 7.86-7.83 (m, 2H), 7.77-7.73 (m,2H), 7.67-7.63 (m, 1H), 7.59 (t, 1H), 6.70-6.67 (m, 1H), 6.55 (dt, 1H),3.96 (s, 3H), 2.20 (s, 3H); LC-MS (ESI): Calculated mass: 424.45;Observed mass: 425.2 [M+H]⁺ (rt: 0.23 min).

Example 155N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamidea) N-(3-nitro-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

To a solution of N-(3-bromo-5-nitrophenyl)acetamide (5 g, 19.3 mmol) inDMF (50 ml) were added 1,2,4-triazole (3.3 g, 48.25 mmol, 2.5 eq.),copper(I) oxide (0.56 g, 3.86 mmol, 0.2 eq.) and cesium carbonate (12.5g, 38.6 mmol, 2 eq.) and the mixture was heated at 90° C. for 48 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off and the residue was purified by column chromatography(60-120 silica gel, 30% ethyl acetate in hexane) to give the product in86% yield (4.1 g). LC-MS (ESI): Calculated mass: 247.21; Observed mass:248.0 [M+H]⁺ (rt: 0.257 min).

b) N-(3-amino-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 155(a) (4.1 g, 16.6 mmol) inTHF (50 ml) and methanol (10 ml) were added ammonium chloride (0.88 g,16.6 mmol) and zinc (1.08 g, 16.6 mmol). The mixture was stirred at RTovernight and filtered. The filtrate was diluted with water andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (60-120 silica gel, 3%methanol in DCM) to give the product in 94% yield (3.4 g).

c)N-(3-(4-bromo-2-nitrophenylamino)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

A solution of the compound of Example 155(b) (3.43 g, 15.67 mmol),4-bromo-1-fluoro-2-nitrobenzene (3.4 g, 15.67 mmol, 1.0 eq.) andpotassium fluoride (0.91 g, 15.67 mmol, 1.5 eq.) in DMF (5 ml) washeated at 80° C. for 7 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 4% methanol in DCM) to givethe product in 80% yield (5.2 g).

d)N-(3-(2-amino-4-bromophenylamino)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 155(c)N-(3-(4-bromo-2-nitro-phenylamino)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide(5.2 g, 12.5 mmol) in ethanol (100 ml) were added calcium chloride (2.78g, 25 mmol, 2 eq.) and iron powder (1.3 g, 25 mmol, 2 eq.) and themixture was heated at 100° C. for 4 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off and the crude residue was directly used for the next step.

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(1H-1,2,4-triazol-1-yl)phenyl)-acetamide

A mixture of the compound of Example 155(d) (4.84 g, 12.5 mmol) andformic acid (10 ml) was heated at 80° C. for 2 h. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 85%yield (4.2 g).

f)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

A solution of the compound of Example 155(e) (100 mg, 0.25 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62mg, 0.3 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (35 mg, 0.03 mmol, 0.12 eq.) and aqueous sodiumcarbonate (0.53 g, 0.5 mmol, 2.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby preparative HPLC to give the product in 50% yield (50 mg). ¹H NMR(400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.36 (s, 1H), 8.77 (s, 1H), 8.28(s, 1H), 8.19-8.18 (m, 2H), 8.00-7.93 (m, 4H), 7.72 (d, 1H), 7.60 (dd,1H), 3.86 (s, 3H), 2.11 (s, 3H); LC-MS (ESI): Calculated mass: 398.42;Observed mass: 399.4 [M+H]⁺ (rt: 0.13 min).

Example 156N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(thiazol-2-yl)phenyl)acetamidea)N-(3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide (2.1 g, 8.1 mmol) in1,2-dimethoxyethane (25 ml) was degassed by N₂ bubbling for 5 min.Bis(pinacolato)diboron (3.09 g, 12.15 mmol, 1.3 eq.) was added and themixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.066 g, 0.081mmol, 0.1 eq.) and potassium acetate (2.38 g, 24.3 mmol, 3 eq.) wereadded and the procedure of Example 1(d) was followed. The crude residueof the product was purified by column chromatography (60-120 silica gel,30% ethyl acetate in hexane) to give the product in 60% yield (1.5 g).

b) N-(3-nitro-5-(thiazol-2-yl)phenyl)acetamide

A solution of the compound of Example 156(a) (2.8 g, 9.14 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.2-Bromothiazole (1 g, 9.14 mmol, 1 eq.) was added and the mixture wasdegassed for another 5 min. Pd(dppf)Cl₂ (0.74 g, 0.91 mmol, 0.1 eq.) andaqueous sodium carbonate (1.9 g, 18.2 mmol, 2 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by column chromatography (60-120 silica gel, 40% ethylacetate in hexane) to give the product in 33% yield (0.8 g). ¹H NMR (300MHz, DMSO-d₆): δ 10.64 (s, 1H), 8.65 (t, 1H), 8.55 (t, 1H), 8.34 (t,1H), 8.04 (d, 1H), 7.94 (d, 1H), 2.13 (s, 3H).

c) N-(3-amino-5-(thiazol-2-yl)phenyl)acetamide

To a solution of the compound of Example 156(b) (0.8 g, 3.03 mmol) inmethanol (25 ml) and ethyl acetate (10 ml) was added 10% Pd/C (300 mg,0.1 eq.) and the reaction vessel was purged with nitrogen gas for 5 min.The mixture was then hydrogenated with H₂ balloon for 12 h. The mixturewas filtered through a pad of celite and the filtrate was concentratedto afford the compound in 71% yield (0.5 g). ¹H NMR (300 MHz, DMSO-d₆):δ 9.83 (s, 1H), 7.86-7.85 (m, 1H), 7.71-7.70 (m, 1H), 7.35 (s, 1H), 7.04(s, 1H), 6.88 (s, 1H), 5.45 (br s, 2H), 2.03 (s, 3H).

d) N-(3-(4-bromo-2-nitrophenylamino)-5-(thiazol-2-yl)phenyl)acetamide

A solution of the compound of Example 156(c) (0.5 g, 2.14 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.47 g, 2.14 mmol, 1.0 eq.) andpotassium fluoride (0.19 g, 3.21 mmol, 1.5 eq.) in DMF was heated at 80°C. for 7 h. The mixture was quenched and extracted as in Example 1(d).The solvent was distilled off and the residue was purified by columnchromatography (60-120 silica gel, 40% ethyl acetate in hexane) to givethe product in 24% yield (0.22 g).

e) N-(3-(2-amino-4-bromophenylamino)-5-(thiazol-2-yl)phenyl)acetamide

To a solution of the compound of Example 156(d) (0.22 g, 0.507 mmol) inTHF (15 ml) were added a solution of ammonium chloride (0.11 g, 2.02mmol, 4 eq.) in water (5 ml) and zinc (0.13 g, 2.02 mmol, 4 eq.). Themixture was stirred at RT overnight and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 83% yield (0.17 g).

f)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(thiazol-2-yl)phenyl)acetamide

A mixture of the compound of Example 156(e) (0.17 g, 0.42 mmol) andformic acid (3 ml) was heated at 80° C. for 2 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 86%yield (0.15 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 8.77 (s,1H), 8.32 (s, 1H), 8.07-8.00 (m, 3H), 7.90-7.87 (m, 2H), 7.66-7.63 (m,1H), 7.55 (s, 1H), 2.13 (s, 3H).

g)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(thiazol-2-yl)phenyl)acetamide

A solution of the compound of Example 156(f) (0.2 g, 0.48 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.15 g, 0.73 mmol, 1.5 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (0.11 g, 0.096 mmol, 0.2 eq.) and aqueoussodium carbonate (0.1 g, 0.96 mmol, 2.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 1.5% yield (3mg). ¹H NMR (300 MHz, CD₃OD): δ 8.20-8.11 (m, 2H), 8.05-7.82 (m, 5H),7.68-7.61 (m, 3H), 7.55-7.45 (m, 1H), 3.88 (s, 3H), 2.12 (s, 3H); LC-MS(ESI): Calculated mass: 414.48; Observed mass: 415.0 [M+H]⁺ (rt: 0.31min).

Example 157N-(3-(1H-indol-3-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamidea) N-(3-nitro-5-(1-(phenylsulfonyl)-1H-indol-3-yl)phenyl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide (0.38 g, 1.48 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.1-(Phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(0.68 g, 1.77 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(dppf)Cl₂ (0.12 g, 0.148 mmol, 0.1 eq.) and aqueoussodium carbonate (0.47 g, 4.45 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by column chromatography (60-120 silica gel, 30% ethylacetate in hexane) to give the product in 77% yield (0.5 g).

b) N-(3-amino-5-(1-(phenylsulfonyl)-1H-indol-3-yl)phenyl)acetamide

To a solution of the compound of Example 157(a) (1 g, 2.29 mmol) inmethanol (10 ml) was added 10% Pd/C (100 mg, 0.1 eq.) and the reactionvessel was purged with nitrogen gas for 5 min. The mixture was thenhydrogenated with H₂ balloon for 12 h. The mixture was filtered througha pad of celite and the filtrate was concentrated to afford the compoundin 89% yield (0.83 g).

c)N-(3-(4-bromo-2-nitrophenylamino)-5-(1-(phenylsulfonyl)-1H-indol-3-yl)-phenyl)acetamide

A solution of the compound of Example 157(b) (0.83 g, 2.04 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.45 g, 2.04 mmol, 1.0 eq.) andpotassium fluoride (0.12 g, 2.04 mmol, 1.0 eq.) in DMF (10 ml) washeated at 130° C. for 5 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 30% ethyl acetate inhexane) to give the product in 48% yield (0.6 g).

d)N-(3-(2-amino-4-bromophenylamino)-5-(1-(phenylsulfonyl)-1H-indol-3-yl)-phenyl)acetamide

To a solution of the compound of Example 157(c) (0.61 g, 1 mmol) in THF(10 ml) and methanol (10 ml) were added a solution of ammonium chloride(0.53 g, 10 mmol, 10 eq.) in water (5 ml) and zinc (0.63 g, 10 mmol, 10eq.). The mixture was stirred at RT for 6 h and filtered. The filtratewas diluted with water and extracted as in Example 1(d). The solvent wasdistilled off to give the product in 70% yield (0.4 g).

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(1-(phenylsulfonyl)-1H-indol-3-yl)phenyl)acetamide

A mixture of the compound of Example 157(d) (0.4 g, 0.7 mmol) and formicacid (10 ml) was heated at 100° C. for 30 min. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 73%yield (0.3 g).

f)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1-(phenylsulfonyl)-1H-indol-3-yl)phenyl)acetamide

A solution of the compound of Example 157(e) (0.3 g, 0.5 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.13 g, 0.62 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (0.057 g, 0.05 mmol, 0.1 eq.) and aqueoussodium carbonate (0.16 g, 1.54 mmol, 3.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by column chromatography (60-120 silica gel, 50% ethylacetate in hexane) to give the product in 100% yield (0.29 g). LC-MS(ESI): Calculated mass: 586.66; Observed mass: 587.2 [M+H]⁺ (rt: 1.53min).

g)N-(3-(1H-indol-3-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide

To a solution of the compound of Example 157(f) (0.3 g, 0.5 mmol, 1 eq.)in THF (10 ml) and methanol (10 ml) was added cesium carbonate (0.33 g,1 mmol, 2 eq.) and the mixture was stirred at RT for 12 h. The mixturewas quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 7% yield (15 mg). ¹H NMR (400 MHz,DMSO-d₆): δ 11.52 (s, 1H), 10.33 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H),8.04-7.89 (m, 4H), 7.68 (d, 1H), 7.60-7.58 (m, 2H), 7.49-7.47 (m, 3H),7.21-7.13 (m, 2H), 3.88 (s, 3H), 2.13 (s, 3H); LC-MS (ESI): Calculatedmass: 446.50; Observed mass: 447.1 [M+H]⁺ (rt: 0.55 min).

Example 158N-(3-(6-methoxypyridin-3-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamidea) N-(3-(6-methoxypyridin-3-yl)-5-nitrophenyl)acetamide

A solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.86 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min.(6-Methoxypyridin-3-yl)boronic acid (0.77 g, 5.0 mmol, 1.3 eq.) wasadded and the mixture was degassed for 5 min. Pd(dppf)Cl₂ (0.630 g, 0.77mmol, 0.2 eq.) and aqueous sodium carbonate (1.23 g, 11.58 mmol, 3.0eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by column chromatography(60-120 silica gel, 40% ethyl acetate in hexane) to give the the productin 81% yield (0.9 g).

b) N-(3-amino-5-(6-methoxypyridin-3-yl)phenyl)acetamide

To a solution of the compound of Example 158(a) (0.9 g, 3.13 mmol) inmethanol (50 ml) was added 10% Pd/C (250 mg) and the reaction vessel waspurged with nitrogen gas for 5 min. The mixture was then hydrogenatedwith H₂ balloon for a period of 4 h. The mixture was filtered through apad of celite and the filtrate was concentrated to afford the compoundin 99% yield (0.8 g).

c)N-(3-((4-bromo-2-nitrophenyl)amino)-5-(6-methoxypyridin-3-yl)phenyl)acetamide

A solution of the compound of Example 158(b) (0.8 g, 3.11 mmol),4-bromo-1-fluoro-2-nitrobenzene (0.68 g, 3.11 mmol, 1.0 eq.) andpotassium fluoride (0.18 g, 3.111 mmol, 1.0 eq.) in DMF (5 ml) washeated at 90° C. for 20 h. The mixture was quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby column chromatography (60-120 silica gel, 40% ethyl acetate inhexane) to give the product in 42% yield (0.6 g). LC-MS (ESI):Calculated mass: 457.28; Observed mass: 458.9 [M+H]⁺ (rt: 1.71 min).

d)N-(3-((2-amino-4-bromophenyl)amino)-5-(6-methoxypyridin-3-yl)phenyl)-acetamide

To a solution of the compound of Example 158(c) (0.3 g, 0.66 mmol) inethanol (20 ml) and water (5 ml) were added calcium chloride (0.73 g,6.6 mmol, 10 eq.) and iron powder (0.36 g, 6.6 mmol, 10 eq.) and themixture was heated at 90° C. for 6 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off and the crude residue was directly used for the next step.

e)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(6-methoxypyridin-3-yl)phenyl)-acetamide

A mixture of the compound of Example 158(d) (0.26 g, 0.61 mmol) andformic acid (5 ml) was heated at 100° C. for 2 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and the residue was purified bycolumn chromatography (60-120 silica gel, 10% methanol in chloroform) togive the product in 86% yield (0.23 g). LC-MS (ESI): Calculated mass:437.29; Observed mass: 438.0 [M+H]⁺ (rt: 1.52 min).

f)N-(3-(6-methoxypyridin-3-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamide

A solution of the compound of Example 158(e) (0.22 g, 0.5 mmol) in1,2-dimethoxyethane (20 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.11 g, 0.55 mmol, 1.1 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (0.116 g, 0.1 mmol, 0.2 eq.) and aqueous sodiumcarbonate (0.16 g, 1.5 mmol, 3.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby preparative HPLC to give the product in 18% yield (40 mg). ¹H NMR(300 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.82 (s, 1H), 8.55 (s, 1H), 8.23 (s,1H), 8.1-8.04 (m, 2H), 7.98-7.91 (m, 2H), 7.85 (s, 1H), 7.74-7.65 (m,3H), 6.97 (d, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.12 (s, 3H); LC-MS(ESI): Calculated mass: 438.48; Observed mass: 439.1 [M+H]⁺ (rt: 0.4min).

Example 159N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)propionamide

To a solution of the compound of Example 29(a) (0.5 g, 1.3 mmol) in DMF(10 ml) was added HATU (0.98 g, 2.6 mmol, 2.0 eq.) followed by DIPEA(0.5 g, 3.9 mmol, 3 eq.) and propionic acid (0.19 g, 2.6 mmol, 2.0 eq.).The mixture was stirred for 4 h and then quenched and extracted as inExample 1(d). The solvent was distilled off and the residue was purifiedby preparative HPLC to give the product in 9% yield (50 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.12 (s, 1H), 8.9-8.8 (s, 1H), 8.6 (d, 1H), 8.2 (s,1H), 8.12 (s, 1H), 7.95 (d, 1H), 7.89-7.82 (m, 2H), 7.8-7.7 (m, 2H),7.55 (s, 1H), 7.45-7.40 (m, 1H), 7.3-7.22 (m, 1H), 6.6-6.52 (s, 1H), 2.4(quartet, 2H), 1.15 (t, 3H); LC-MS (ESI): Calculated mass: 443.45;Observed mass: 444.1 [M+H]⁺ (rt: 1.58 min).

Example 160N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)isobutyramide

The compound was prepared from the compound of Example 29(a) using theprocedures of Example 159. ¹H NMR (300 MHz, DMSO-d₆): δ 10.28 (s, 1H),8.8 (s, 1H), 8.58 (d, 1H), 8.22 (d, 1H), 8.11 (s, 1H), 7.95 (d, 1H),7.92 (d, 1H), 7.87 (d, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H),7.45 (d, 1H), 7.25 (s, 1H), 6.55-6.54 (m, 1H), 2.67-2.58 (m, 1H), 1.12(d, 6H); LC-MS (ESI): Calculated mass: 457.47; Observed mass: 458.1[M+H]⁺ (rt: 1.6 min).

Example 161N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamide

The compound was prepared from the compound of Example 29(a) using theprocedures of Example 159. ¹H NMR (300 MHz, DMSO-d₆): δ 10.63 (s, 1H),8.72 (s, 1H), 8.57 (d, 1H), 8.21 (d, 1H), 8.08 (s, 1H), 7.93-7.74 (m,5H), 7.52 (s, 1H), 7.46-7.39 (m, 1H), 7.29-7.23 (m, 1H), 6.55 (s, 1H),1.85-1.79 (m, 1H), 0.87 (d, 4H); LC-MS (ESI): Calculated mass: 455.46;Observed mass: 456.1 [M+H]⁺ (rt: 1.58 min).

Example 162N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)pivalamide

The compound was prepared from the compound of Example 29(a) using theprocedures of Example 159. ¹H NMR (400 MHz, DMSO-d₆): δ 9.65 (s, 1H),8.74 (s, 1H), 8.0 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.01 (s, 1H),7.95-7.92 (m, 1H), 7.84-7.81 (m, 1H), 7.78-7.72 (m, 2H), 7.54 (s, 1H),7.48-7.42 (m, 1H), 7.29-7.25 (m, 1H), 6.57-6.56 (m, 1H), 1.27 (s, 9H);LC-MS (ESI): Calculated mass: 471.5; Observed mass: 472.2 [M+H]⁺ (rt:1.68 min).

Example 163N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-morpholinoacetamide

To a solution of the compound of Example 29(a) (0.1 g, 0.26 mmol) in DMF(3 ml) was added EDC (74 mg, 0.39 mmol, 1.5 eq.), HOBt (70 mg, 0.52mmol, 2 eq.) followed by DIPEA (0.1 g, 0.77 mmol, 3 eq.) and2-morpholinoacetic acid (Intermediate Example 10) (56 mg, 0.39 mmol, 1.5eq.). The mixture was stirred for 12 h and then quenched and extractedas in Example 1(d). The solvent was distilled off and the crude residuewas purified by preparative HPLC to give the product in 27% yield (36mg). ¹H NMR (400 MHz, D₂O): δ 8.74 (s, 1H), 8.60 (d, 1H), 8.24 (d, 1H),8.14 (s, 1H), 7.96-7.91 (m, 2H), 7.84-7.76 (m, 3H), 7.57 (s, 1H),7.49-7.40 (m, 1H), 7.35-7.22 (m, 1H), 6.56 (m, 1H), 3.66 (t, 4H),3.61-3.59 (m, 4H), 3.21 (s, 2H); LC-MS (ESI): Calculated mass: 514.53;Observed mass: 515.1 [M+H]⁺ (rt: 0.53 min).

Example 164N-(2′,4′-difluoro-5-(5-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 17(e) (0.7 g, 1.8 mmol),4-azido-1-methylpiperidine (0.3 g, 2.17 mmol, 1.2 eq.), sodium ascorbate(0.35 g, 1.8 mmol, 1.0 eq.) and copper sulfate pentahydrate (0.22 g, 0.9mmol, 0.5 eq.) in DMSO, DCM and water (1:1:1, 3 ml) was stirred for 12 hat RT. The mixture was quenched with water and the precipitate formedwas filtered and dried to give the crude product which wasrecrystallized from diethyl ether to give the product in 71% yield (0.67g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 8.75 (s, 2H), 8.28 (d,1H), 8.11 (s, 1H), 7.95-7.92 (m, 1H), 7.81-7.74 (m, 2H), 7.53 (s, 1H),7.45 (m, 1H), 7.27 (m, 1H), 3.66-3.62 (m, 1H), 3.26-3.22 (m, 4H), 2.87(s, 3H), 2.27-2.22 (m, 4H), 2.12 (m, 3H); LC-MS (ESI): Calculated mass:527.57; Observed mass: 528.2 [M+H]⁺ (rt: 0.19 min).

Example 165N-(2′,4′-difluoro-5-(5-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)2′,4′-difluoro-5-(5-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine

A solution of the compound of Example 164 (0.48 g, 0.91 mmol) in 6 N HCl(10 ml) was heated at 70° C. for 3 h. The mixture was quenched withNaHCO₃ solution and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 27% yield (0.12 g).

b)N-(2′,4′-difluoro-5-(5-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of the compound of Example 165(a) (60 mg, 0.123 mmol) inDCM (2 ml) was added pyridine (19 mg, 0.246 mmol, 2.0 eq.) followed byethanesulfonyl chloride (19 mg, 0.148 mmol, 1.2 eq.). The reaction wasmonitored by LCMS. After completion of the reaction the solvent wasremoved under reduced pressure and the crude product was purified byflash chromatography (using 2% methanol in chloroform) to give theproduct in 13% yield (9 mg). LC-MS (ESI): Calculated mass: 577.65;Observed mass: 578.2 [M+H]⁺ (rt: 0.42 min).

Example 166N-(2′,4′-difluoro-5-(5-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 164 using theprocedures of Example 165 and cyclopropane sulfonyl chloride. LC-MS(ESI): Calculated mass: 553.61; Observed mass: 554.2 [M+H]⁺ (rt: 0.57min).

Example 167N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from compound of Intermediate Example 12 usingthe procedure of Example 8. ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H),9.12 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 8.02-7.97 (m, 2H), 7.81 (s,1H), 7.75-7.67 (m, 3H), 7.55 (s, 1H), 7.47-7.41 (m, 1H), 7.29-7.22 (m,1H), 4.52-4.45 (m, 1H), 2.10 (s, 3H), 1.45 (d, 6H); LC-MS (ESI):Calculated mass: 471.5; Observed mass: 471.6 [M+H]⁺ (rt: 1.4 min).

Example 168N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamidea)N-(5-((4-acetyl-2-nitrophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 1(e) (0.6 g, 2.28 mmol),1-(4-fluoro-3-nitrophenyl)ethanone (0.4 g, 2.28 mmol, 1.0 eq.) andpotassium fluoride (0.26 g, 4.56 mmol, 2.0 eq.) in DMF was heated at 80°C. for 7 h. The mixture was quenched and extracted as in Example 1(d).The solvent was distilled off and the residue was purified by columnchromatography (60-120 silica gel, 1% methanol in chloroform) to givethe product in 68% yield (0.66 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.18(s, 1H), 9.83 (s, 1H), 8.63 (d, 1H), 8.01 (m, 1H), 7.71 (s, 1H), 7.59(m, 2H), 7.35 (m, 1H), 7.27-7.16 (m, 3H), 2.52 (s, 3H), 2.05 (s, 3H).

b)(E)-N-(5-((4-(3-(dimethylamino)acryloyl)-2-nitrophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 168(a) (0.66 g, 1.55 mmol) inDMF (4 ml) and ethanol (4 ml) was added DMF dimethylacetal (7 ml) andstirred at 110° C. for 12 h. The mixture was extracted as in Example1(d). The solvent was distilled off to give the product in 89% yield(0.66 g) which was directly used for the next step.

c)N-(2′,4′-difluoro-5-((4-(1-methyl-1H-pyrazol-3-yl)-2-nitrophenyl)amino)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 168(b) (0.66 g, 1.37 mmol) inethanol (15 ml) was added methyl hydrazine (7 ml) and stirred at RTovernight. The mixture was quenched with chilled water and the solidformed was filtered, washed with water and used for the next step. ¹HNMR (300 MHz, DMSO-d₆): δ 10.12 (s, 1H), 9.52 (s, 1H), 8.19 (d, 1H),7.73-7.60 (m, 2H), 7.59-7.54 (m, 2H), 7.46-7.35 (m, 3H), 7.30-7.14 (m,2H), 6.44 (d, 1H), 3.85 (s, 3H), 2.05 (s, 3H).

d)N-(5-((2-amino-4-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2′,4′-difluoro-15 [1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 168(c) (0.5 g, 1.07 mmol) inTHF (20 ml) were added a solution of ammonium chloride (0.23 g, 4.28mmol, 4 eq.) in water (10 ml) and zinc (0.28 g, 4.28 mmol, 4 eq.). Themixture was stirred at RT for 4 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 65% yield (0.3 g). LC-MS (ESI): Calculatedmass: 433.45; Observed mass: 434.1 [M+H]⁺ (rt: 0.49 min).

e)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 168(d) (0.3 g, 0.69 mmol) andformic acid (3 ml) was heated at 100° C. for 2 h. The formic acid wasdistilled off and the crude was extracted with in ethyl acetate. Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 9% yield (28 mg). ¹H NMR (300 MHz, DMSO-d₆):δ 10.42 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.83-7.72 (m,3H), 7.54-7.42 (m, 4H), 7.30-7.25 (m, 1H), 6.45 (d, 1H), 3.9 (s, 3H),2.13 (s, 3H); LC-MS (ESI): Calculated mass: 443.45; Observed mass: 443.7[M+H]⁺ (RT: 1.37 min).

Example 169N-(5-(5-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea)N-(5-((4-(4,5-dihydro-1H-imidazol-2-yl)-2-nitrophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 22(a) (200 mg, 0.49 mmol) inDCM (10 ml) at 0° C. was added ethylene diamine (0.036 ml, 0.54 mmol,1.1 eq.) followed by N-bromosuccinimide (95 mg, 0.54 mmol, 1.1 eq.). Themixture was stirred for 12 h, quenched with water and extracted as inExample 2(b). The solvent was distilled off and the residue was purifiedcolumn chromatography (60-120 silica gel, 20% methanol in chloroform) togive the product in 50% yield (0.11 g). LC-MS (ESI): Calculated mass:451.43; Observed mass: 452.1 [M+H]⁺ (rt: 0.63 min).

b)N-(5-((2-amino-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 169(a) (0.11 g, 0.23 mmol) inTHF (10 ml) were added a solution of ammonium chloride (50 mg, 0.93mmol, 4 eq.) in water (10 ml) and zinc (60 mg, 0.93 mmol, 4 eq.). Themixture was stirred at RT for 4 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 88% yield (85 mg). LC-MS (ESI): Calculatedmass: 421.44; Observed mass: 422.2 [M+H]⁺ (rt: 0.49 min).

c)N-(5-(5-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 169(b) (80 mg, 0.19 mmol) andformic acid (3 ml) was heated at 100° C. for 4 h. The formic acid wasdistilled off and the crude was extracted with in ethyl acetate. Thesolvent was distilled off and the residue was purified by preparativeHPLC to give the product in 12% yield (10 mg). ¹H NMR (400 MHz, D₂O): δ8.75 (s, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.84-7.79 (m, 2H), 7.74 (s,1H), 7.66-7.6 (m, 1H), 7.47 (s, 1H), 7.29-7.23 (m, 1H), 7.19-7.14 (m,1H), 3.99 (m, 4H), 2.06 (s, 3H); LC-MS (ESI): Calculated mass: 431.44;Observed mass: 432.1 [M+H]⁺ (rt: 0.36 min).

Example 170N-(4′-fluoro-5-(5-(6-fluoropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was synthesized using the procedures of Example 53. LC-MS(ESI): Calculated mass: 440.44; Observed mass: 441.1 [M+H]⁺ (rt: 1.57min).

Example 171N-(3-(5-(1-Ethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(l1H-pyrrol-1-yl)phenyl)acetamide

To a solution of the compound of Example 87(g) (1.5 g, 3.8 mmol) in1,2-dimethoxyethane (40 ml), the compound of Intermediate Example 13(1.68 g, 7.59 mmol, 2 eq.), sodium carbonate (1 g, 9.5 mmol, 2.5 eq.)and water (4 ml) were added and the mixture was degassed for 15 min (N₂bubbling). Pd(PPh₃)₄ (0.9 g, 0.76 mmol, 0.2 eq.) was added and themixture was heated at 100° C. for 2 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified column chromatography afford the compound in 74%yield (1.15 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.86 (m, 1H), 8.26 (m, 1H),7.99-7.94 (m, 2H), 7.87-7.80 (m, 2H), 7.72-7.60 (m, 3H), 7.39 (s, 2H),6.31 (s, 2H), 4.15 (quartet, 2H), 2.10 (s, 3H), 1.40 (t, 3H); LC-MS(ESI): Calculated mass: 410.47; Observed mass: 411.2 [M+H]⁺ (rt: 1.11min).

Example 172N-(3-(5-(1-Ethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamidea)3-(5-(1-Ethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

A mixture of 20% NaOH (5 ml) and the compound of Example 171 (0.9 g,2.12 mmol) in 25 ml of ethanol was heated at 90° C. for 2 h. The mixturewas diluted with ethyl acetate (100 ml) and the organic layer was washedwith water (50 ml) and brine (25 ml). The solvent was distilled off andthe residue was purified by column chromatography over silica gel toafford the compound in 78% yield (0.7 g).

b)N-(3-(5-(1-Ethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamide

To a solution of the compound of Example 172(a) (75 mg, 0.2 mmol) in DCM(1 ml) were added pyridine (0.5 ml) and ethanesulfonyl chloride (52 mg,0.4 mmol, 2 eq.) and the mixture was stirred at RT for 12 h. Pyridinewas distilled off and the residue was purified by preparative HPLC toafford the compound in 25% yield (23 mg). ¹H NMR (300 MHz, DMSO-d₆): δ10.31 (s, 1H), 8.74 (s, 1H), 8.26 (s, 1H), 7.98 (d, 2H), 7.69-7.61 (m,3H), 7.42-7.38 (m, 4H), 6.33 (s, 2H), 4.15 (quartet, 2H), 3.16 (quartet,2H), 1.43 (t, 3H), 1.25 (t, 3H); LC-MS (ESI): Calculated mass: 460.55;Observed mass: 461.18 [M+H]⁺ (rt: 1.38 min).

Example 173N-(3-(5-(1-Isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)acetamide

The compound was prepared from the compound of Intermediate Example 12using the procedure of Example 171. ¹H NMR (300 MHz, DMSO-d₆): δ 10.40(s, 1H), 8.67 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H),7.86-7.81 (m, 2H), 7.70-7.59 (m, 3H), 7.41 (s, 2H), 6.32 (s, 2H),4.53-4.49 (m, 1H), 2.12 (s, 3H), 1.46 (d, 6H); LC-MS (ESI): Calculatedmass: 424.5; Observed mass: 425.2 [M+H]⁺ (rt: 1.34 min).

Example 174N-(3-(5-(1-Isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(lH-pyrrol-1-yl)phenyl)methanesulfonamide a)3-(5-(1-Isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)aniline

A mixture of 20% NaOH (5 ml) and the compound of Example 173 (1 g, 2.43mmol) in 25 ml ethanol was heated at 90° C. for 2 h. The mixture wasdiluted with ethyl acetate (100 ml) and the organic layer was washedwith water (50 ml) and brine (25 ml). The solvent was distilled off andthe crude was purified by column chromatography over silica gel toafford the compound in 93% yield (0.75 g).

b)N-(3-(5-(1-Isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)methanesulfonamide

To a solution of the compound of Example 174(a) (100 mg, 0.26 mmol) inDCM (1 ml) were added pyridine (0.5 ml) and ethanesulfonyl chloride (60mg, 0.52 mmol, 2 eq.) and the mixture was stirred at RT for 12 h.Pyridine was distilled off and the residue was purified by preparativeHPLC to afford the compound in 8% yield (10 mg). ¹H NMR (300 MHz,CD₃OD): δ 9.20 (s, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.80(s, 2H), 7.62 (s, 1H), 7.49 (m, 2H), 7.31 (m, 2H), 6.35 (m, 2H),4.65-4.51 (m, 1H), 3.14 (s, 3H), 1.55 (d, 6H); LC-MS (ESI): Calculatedmass: 461.0; Observed mass: 460.55 [M+H]⁺ (rt: 1.44 min).

Example 175N-(3-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrrol-1-yl)phenyl)ethanesulfonamide

The compound was prepared from the compound of Example 173 using theprocedure of Example 174. ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s, 1H), 8.16(s, 1H), 7.99-7.93 (m, 2H), 7.77 (s, 2H), 7.58 (s, 1H), 7.47 (m, 2H),7.30 (m, 2H), 6.35 (m, 2H), 4.60-4.51 (m, 1H), 3.30 (quartet, 2H),1.56-1.54 (d, 6H), 1.38 (t, 3H); LC-MS (ESI): Calculated mass: 474.58;Observed mass: 475.1 [M+H]⁺ (rt: 1.50 min).

Example 176N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)propionamide

To a solution of propionic acid (20 mg, 0.274 mmol) in DMF (2 ml) wasadded HATU (155 mg, 0.41 mmol, 1.5 eq.) and the mixture was stirred atRT for 0.5 h. The compound of Example 132(a) (110 mg, 0.274 mmol) andDIPEA (0.15 ml, 0.821 mmol, 3 eq.) were added and the mixture wasstirred for 12 h, quenched with water and extracted with DCM (3×50 ml).The combined organic layer was washed with water to obtain precipitatewhich was filtered. The crude product was purified by preparative HPLCto give the product (14 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H),8.92 (s, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.33-8.31 (m, 2H), 8.04 (d,1H), 7.89 (d, 1H), 7.75-7.69 (m, 2H), 7.48-7.42 (m, 1H), 7.29-7.25 (m,1H), 3.90 (s, 3H), 2.40 (quartet, 2H), 1.11 (t, 3H); LC-MS (ESI):Calculated mass: 458.46; Observed mass: 459.1 [M+H]⁺ (rt: 1.44 min).

Example 177N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamide

The compound was prepared using the procedure of Example 176. ¹H NMR(400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 8.94 (s, 1H), 8.72 (d, 1H), 8.41(d, 1H), 8.31 (d, 2H), 8.04 (s, 1H), 7.88 (br s, 1H), 7.72-7.68 (m, 2H),7.47-7.41 (m, 1H), 7.29-7.25 (m. 1H), 3.89 (s, 3H), 1.85 (m, 1H), 0.84(d, 4H); LC-MS (ESI): Calculated mass: 470.4; Observed mass: 471.1[M+H]⁺ (rt: 1.52 min).

Example 178N-(2′,4′-difluoro-5-(6-(6-fluoropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 131(c) (330 mg, 0.75 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.(6-Fluoropyridin-3-yl)boronic acid (130 mg, 0.9 mmol, 1.2 eq.) was addedand the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (120 mg,0.15 mmol, 0.2 eq.) and aqueous sodium carbonate (290 mg, 2.7 mmol, 3.0eq.) were added and the procedure of Example 1(d) was followed. Thecrude residue of the product was purified by preparative HPLC to givethe product. ¹H NMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 9.03 (s, 1H),8.79 (d, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.43 (dt, 1H), 8.30 (s, 1H),7.87 (s, 1H), 7.70 (s, 2H), 7.47-7.26 (m, 3H), 2.07 (s, 3H); LC-MS(ESI): Calculated mass: 459.4; Observed mass: 460.1 [M+H]⁺ (rt: 1.53min).

Example 179N-(5-(6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared using the procedures of Example 148 startingfrom N-(3-bromo-5-nitrophenyl)acetamide (0.8 g, 3.089 mmol) and2-Fluoro-4-methoxy-phenyl)boronic acid (0.63 g, 3.71 mmol, 1.2 eq.). ¹HNMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.05 (s, 1H), 9.02 (d, 1H),8.67 (d, 2H), 8.26 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.68 (s, 1H),7.59 (t, 1H), 7.04-6.95 (m, 2H), 6.64 (t, 1H), 3.85 (s, 3H), 2.13 (s,3H); LC-MS (ESI): Calculated mass: 442.45; Observed mass: 443.1 [M+H]⁺(rt: 1.42 min).

Example 180N-(2′-fluoro-4′-methoxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 179(e) (250 mg, 0.549 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(137 mg, 0.66 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (63 mg, 0.0549 mmol, 0.1 eq.) and aqueoussodium carbonate (117 mg, 1.1 mmol, 2.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the product in 90% yield (225mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.92 (s, 1H), 8.71 (d,1H), 8.41 (d, 1H), 8.30 (s, 1H), 8.25 (t, 1H), 8.04 (s, 1H), 7.84 (d,1H), 7.67 (s, 1H), 7.58 (t, 1H), 7.03-6.93 (m, 2H), 3.90 (s, 3H), 3.84(s, 3H), 2.11 (s, 3H); LC-MS (ESI): Calculated mass: 456.47; Observedmass: 456.6 [M+H]⁺ (rt: 1.07 min).

Example 181N-(2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamidea)N-(2′,4′-difluoro-5-((5-iodo-3-nitropyridin-2-yl)amino)-[1,1′-biphenyl]-3-yl)-acetamide

A solution of the compound of Example 1(e) (2.58 g, 9.85 mmol),2-chloro-5-iodo-3-nitropyridine of Intermediate Example 14 (2.8 g, 9.85mmol, 1.0 eq.) and potassium fluoride (0.57 g, 9.85 mmol, 1.0 eq.) inDMF (30 ml) was heated at 130° C. for 5 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off and theresidue was purified by column chromatography (60-120 silica gel, 30%ethyl acetate in hexane) to give the product in 40% yield (2.0 g). ¹HNMR (300 MHz, DMSO-d₆): δ 10.10 (s, 1H), 9.95 (s, 1H), 8.74 (d, 1H),8.66 (d, 1H), 7.88 (s, 1H), 7.60-7.52 (m, 2H), 7.42-7.34 (m, 2H),7.24-7.21 (m, 1H), 2.07 (s, 3H), LC-MS (ESI): Calculated mass: 510.2;Observed mass: 510.9 [M+H]⁺ (rt: 1.75 min).

b)N-(5-((3-amino-5-iodopyridin-2-yl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 181(a) (0.5 g, 0.98 mmol) inTHF (30 ml) were added a solution of ammonium chloride (0.2 g, 3.92mmol, 4 eq.) in water (15 ml) and zinc (0.25 g, 3.92 mmol, 4 eq.). Themixture was stirred at RT for 3 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to give the product in 64% yield (0.3 g). ¹H NMR (400 MHz, DMSO-d₆):δ 9.96 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H), 7.50 (quartet,1H) 7.43 (s, 1H), 7.39-7.33 (m, 1H), 7.28 (s, 1H), 7.22-7.18 (m, 2H),5.39 (s, 2H), 2.05 (s, 3H); LC-MS (ESI): Calculated mass: 480.2;Observed mass: 481.1 [M+H]⁺ (rt: 1.53 min).

c)N-(2′,4′-difluoro-5-(6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 181(b) (3.12 g, 1.5 g) and formicacid (15 ml) was heated at 90° C. for 1 h. Formic acid was thendistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the product in 92%yield (1.4 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.38 (s, 1H), 8.93 (s, 1H),8.63 (s, 2H), 8.21 (s, 1H), 7.89 (s, 1H), 7.74-7.64 (m, 2H), 7.42 (t,1H), 7.26 (t, 1H), 2.11 (s, 3H); LC-MS (ESI): Calculated mass: 490.2;Observed mass: 491.1 [M+H]⁺ (rt: 1.60 min).

d)N-(2′,4′-difluoro-5-(6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 181(c) (1.6 g, 3.265 mmol) inDMF-Et₃N (1:1; 60 ml) was degassed by N₂ bubbling for 15 min. Pd(PPh₃)₄(0.18 g, 0.163 mmol, 0.05 eq.), copper(I) iodide (62 mg, 0.326 mmol, 0.1eq.) and ethynyltrimethylsilane (0.38 g, 3.91 mmol, 1.2 eq.) were addedsequentially and the mixture was stirred for 12 h at RT. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offand the residue was purified by column chromatography (60-120 silicagel, 40% ethyl acetate in hexane) to give the product in 73% yield (1.1g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.02 (s, 1H), 8.52 (d,1H), 8.33 (d, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.73-7.64 (m, 2H), 7.43(m, 1H), 7.26 (m, 1H), 2.11 (s, 3H), 0.27 (s, 9H); LC-MS (ESI):Calculated mass: 460.55; Observed mass: 461.2 [M+H]⁺ (rt: 1.83 min).

e)N-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 181(d) (1.1 g, 2.4 mmol) in THFat 0° C. was added TBAF (1 M in THF; 0.6 ml, 2.4 mmol, 1.0 eq.) and themixture was stirred for 0.5 h. The mixture was filtered over a pad ofsilica and distilled to give crude residue which was purified by columnchromatography (60-120 silica gel, 5% methanol in chloroform) to givethe product in 86% yield (0.8 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s,1H), 9.03 (s, 1H), 8.56 (d, 1H), 8.38 (d, 1H), 8.23 (s, 1H), 7.91 (s,1H), 7.75-7.66 (m, 2H), 7.48-7.41 (m, 1H), 7.30-7.24 (m, 1H), 4.39 (s,1H), 2.07 (s, 3H); LC-MS (ESI): Calculated mass: 388.3; Observed mass:389.2 [M+H]⁺ (rt: 1.49 min).

f)N-(2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 181(e) (0.5 g, 1.28 mmol),4-azido-1-methylpiperidine of Intermediate Example 11 (0.21 g, 1.54mmol, 1.2 eq.), sodium ascorbate (0.25 g, 1.28 mmol, 1.0 eq.) and coppersulfate pentahydrate (0.16 g, 0.6 mmol, 0.5 eq.) in DMSO, DCM and water(2:5:2, 9 ml) was stirred for 12 h at RT. The mixture was quenched withwater and the precipitate formed was filtered and dried to give thecrude product which was purified by preparative HPLC to give the productin 74% yield (0.5 g). ¹H NMR (300 MHz, CDCl₃): δ 8.94 (d, 1H), 8.56 (d,1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.65 (s,2H), 7.53-7.45 (m, 1H), 7.05-7.49 (m, 1H), 4.68-4.59 (m, 1H), 3.18-3.13(m, 4H), 2.62 (s, 3H), 2.44-2.39 (m, 4H), 2.24 (s, 3H); LC-MS (ESI):Calculated mass: 558.50; Observed mass: 529.2 [M+H]⁺ (rt: 0.39 min).

Example 182N-(2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine

The compound of Example 181 (0.4 g, 0.757 mmol) was added to aqueous 6 NHCl (10 ml) at 0° C. and the mixture was stirred at 70° C. for 3 h. Themixture was quenched with saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate (3×50 ml). The combined organic layerwas washed with water, brine and dried over sodium sulphate and theresidue was purified by column chromatography (60-120 silica gel, 10%methanol in DCM) to give the product in 30% yield (0.11 g). LC-MS (ESI):Calculated mass: 486.52; Observed mass: 487.3 [M+H]⁺ (rt: 0.22 min).

b)N-(2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of the compound of Example 182(a) (55 mg, 0.113 mmol) inDCM was added pyridine (17 mg, 0.226 mmol, 2.0 eq.) followed byethanesulfonyl chloride (17 mg, 0.135 mmol, 1.2 eq.). The reaction wasmonitored by LCMS. After completion of the reaction the solvent wasdistilled off and the crude product was purified by preparative HPLC togive the product in 46% yield (30 mg). ¹H NMR (300 MHz, DMSO-d₆): δ10.31 (s, 1H), 9.01 (s, 1H), 8.97 (d, 1H), 8.84 (s, 1H), 8.62 (s, 1H),7.93 (s, 1H), 7.75-7.71 (m, 2H), 7.48-7.41 9 (m, 2H), 7.27 (m, 1H), 3.45(m, 1H), 2.79 (s, 3H), 2.41-2.34 (m, 4H), 2.28-2.24 (quartet, 2H),1.27-1.22 (m, 4H), 1.03 (t, 3H); LC-MS (ESI): Calculated mass: 578.64;Observed mass: 578.9 [M+H]⁺ (RT: 0.11 min).

Example 183N-(2′,4′-difluoro-5-(6-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamide

To a solution of cyclopropanecarboxylic acid (14 mg, 0.169 mmol, 1.5eq.) in DMF (2 ml) was added HATU (90 mg, 0.226 mmol, 2.0 eq.) and themixture was stirred at RT for 0.5 h. The compound of Example 182(a) (55mg, 0.113 mmol) and DIPEA (45 mg, 0.339 mmol, 3 eq.) were added and themixture was stirred for 12 h, quenched with water and extracted with DCM(3×50 ml). The combined organic layer was washed with water to obtainprecipitate which was filtered. The crude product was purified bypreparative HPLC to give the product in 13% yield (12 mg). ¹H NMR (300MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.98 (s, 2H), 8.83 (s, 1H), 8.62 (s,1H), 8.33 (s, 1H), 8.88 (s, 1H), 7.71-7.66 (m, 2H), 7.46-7.39 (m, 1H),7.28-7.23 (m, 1H), 4.83 (m, 1H), 3.62-3.52 (m, 4H), 2.81 (s, 3H),2.30-2.26 (m, 4H), 1.85 (m, 1H), 0.83 (d, 4H); LC-MS (ESI): Calculatedmass: 554.59; Observed mass: 554.9 [M+H]⁺ (rt: 0.183 min).

Example 184N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamidea)5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,6′-difluoro-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 152 (2.1 g, 4.895 mmol) inethanol (50 ml) was added 10% aqueous solution of NaOH (10 ml) and themixture was heated at 100° C. for 2 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe product in 89% yield (1.6 g).

b)N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

To a solution of the compound of Example 184(a) (50 mg, 0.129 mmol) inDCM was added pyridine (20 mg, 0.258 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (18 mg, 0.155 mmol, 1.2 eq.). The reaction wasmonitored by LCMS. After completion of the reaction the solvent wasdistilled off and the crude product was purified by preparative HPLC togive the product in 50% yield (30 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.32 (s, 1H), 8.76 (s, 1H), 8.61 (d, 1H), 8.24 (d, 1H), 7.93 (dd, 1H),7.79 (s, 1H), 7.76 (d, 1H), 7.61-7.57 (m, 4H), 7.37 (s, 1H), 7.31 (t,2H), 3.19 (s, 3H); LC-MS (ESI): Calculated mass: 465.48; Observed mass:466.1 [M+H]⁺ (rt: 1.47 min).

Example 185N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 152 using theprocedure of Example 184. ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H),8.72 (s, 1H), 8.60 (d, 1H), 8.24 (d, 1H), 7.93 (dd, 1H), 7.76 (t, 2H),7.61-7.54 (m, 3H), 7.39 (s, 1H), 7.31 (t, 2H), 6.56 (t, 1H), 2.40(quartet, 2H), 1.26 (t, 3H); LC-MS (ESI): Calculated mass: 479.5;Observed mass: 480.0 [M+H]⁺ (rt: 1.51 min).

Example 186N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamidea)2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 151 (2.0 g, 4.514 mmol) inethanol (50 ml) was added 10% aqueous solution of NaOH (2.5 ml) and themixture was heated at 100° C. for 2 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe product in 99% yield (1.8 g).

b)N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

To a solution of the compound of Example 186(a) (50 mg, 0.124 mmol) inDCM was added pyridine (20 mg, 0.258 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (29 mg, 0.155 mmol, 2.0 eq.). The reaction wasmonitored by LCMS. After completion of the reaction the solvent wasdistilled off and the crude product was purified by preparative HPLC togive the product in 42% yield (25 mg). ¹H NMR (300 MHz, DMSO-d₆): δ10.34 (s, 1H), 8.76 (s, 1H), 8.22 (s, 1H), 7.97 (d, 2H), 7.66-7.57 (m,5H), 7.36-7.30 (m, 3H), 3.88 (s, 3H), 3.19 (s, 3H); LC-MS (ESI):Calculated mass: 479.50; Observed mass: 480.2 [M+H]⁺ (rt: 1.27 min).

Example 187N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 151 using theprocedure of Example 186. ¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H),8.80 (s, 1H), 8.23 (s, 1H), 7.98 (d, 2H), 7.67 (s, 2H), 7.61 (s, 1H),7.56 (s, 2H), 7.38 (s, 1H), 7.30 (t, 2H), 3.88 (s, 3H), 3.30 (quartet,2H), 1.26 (t, 3H); LC-MS (ESI): Calculated mass: 493.3; Observed mass:494.1 [M+H]⁺ (rt: 1.38 min).

Example 188N-(4′-fluoro-2′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared using the procedures of Example 148 startingfrom N-(3-bromo-5-nitrophenyl)acetamide (0.8 g, 3.089 mmol) and4-Fluoro-2-methoxy-phenyl)boronic acid (0.63 g, 3.71 mmol, 1.2 eq.). ¹HNMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 8.93 (s, 1H), 8.24 (s, 1H),8.07 (s, 1H), 7.98 (d, 2H), 7.71-7.69 (m, 3H), 7.47-7.44 (m, 2H), 7.08(dd, 1H), 6.93 (dt, 1H), 3.88 (s, 3H), 3.17 (s, 3H), 2.08 (s, 3H); LC-MS(ESI): Calculated mass: 455.48; Observed mass: 456.1 [M+H]⁺ (rt: 1.13min).

Example 189N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamidea) N-(2′-fluoro-4′-methoxy-5-nitro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(c) (0.8 g,3.089 mmol) and (2-Fluoro-4-methoxyphenyl)boronic acid (0.63 g, 3.71mmol, 1.2 eq.) using the procedure of Example 148(a) to give the productin 97% yield (0.91 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 8.59(s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.55 (t, 1H), 7.05-6.93 (m, 2H),3.84 (s, 3H), 2.11 (s, 3H).

b) N-(5-amino-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 189(a) (0.9 g,2.96 mmol) using the procedure of Example 148(b) to give the product in97% yield (790 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 9.74 (s, 1H), 7.28 (t,1H), 6.91-6.78 (m, 4H), 6.34 (s, 1H), 5.15 (br s, 2H), 3.77 (s, 3H),1.98 (s, 3H); LC-MS (ESI): Calculated mass: 274.3; Observed mass: 275.2[M+H]⁺ (rt: 0.35 min).

c)N-(5-((4-bromo-2-nitrophenyl)amino)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 189(b) (3 g,10.95 mmol) using the procedure of Example 148(c) to give the crudeproduct in 93% yield (4.82 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.13 (s,1H), 9.43 (s, 1H), 8.23 (d, 1H), 7.68-7.64 (m, 2H), 7.53 (s, 1H), 7.44(t, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 6.98-6.88 (m, 2H), 3.81 (s, 3H),2.06 (s, 3H); LC-MS (ESI): Calculated mass: 474.3; Observed mass: 476.01[M+H]⁺ (rt: 1.85 min).

d)N-(5-((2-amino-4-bromophenyl)amino)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 189(c) (4.8 g,10.13 mmol) using the procedure of Example 148(d) to give the product in93% yield (4.12 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.80 (s, 1H), 7.30 (t,2H), 7.11 (d, 1H), 6.98-6.82 (m, 5H), 6.63 (dd, 1H), 6.52 (s, 1H), 5.09(br s, 2H), 3.77 (s, 3H), 1.98 (s, 3H); LC-MS (ESI): Calculated mass:444.30; Observed mass: 441.0 [M+H]⁺ (rt: 1.66 min).

e)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 189(d) (4 g, 9mmol) using the procedure of Example 148(e) to give the product in 95%yield (3.8 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.38 (s, 1H), 8.69 (s, 1H),7.99 (t, 2H), 7.77 (d, 1H), 7.65-7.44 (m, 4H), 7.01-6.89 (m, 2H), 3.81(s, 3H), 2.09 (s, 3H); LC-MS (ESI): Calculated mass: 454.3.30; Observedmass: 456.0 [M+H]⁺ (rt: 1.68 min).

f)N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′-fluoro-4′-methoxy-15 [1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 189(e) (0.8 g,1.76 mmol) using the procedure of Example 148(f) to give the product in71% yield (0.55 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.34 (s, 1H), 8.84 (s,1H), 8.61 (d, 1H), 8.24 (d, 1H), 8.06 (s, 1H), 7.95-7.93 (m, 1H),7.82-7.77 (m, 3H), 7.61 (t, 1H), 7.51 (s, 1H), 7.04-6.94 (m, 2H), 6.57(t, 1H), 3.84 (s, 3H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass:441.4; Observed mass: 442.1 [M+H]⁺ (rt: 1.44 min).

Example 190N-(2′-fluoro-4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 189(e) (0.25 g, 0.55 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.14 g, 0.66 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (63 mg, 0.055 mmol, 0.1 eq.) and aqueous sodiumcarbonate (0.12 g, 1.1 mmol, 2.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby preparative HPLC to give the product in 90% yield (0.23 g). ¹H NMR(400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 9.08 (s, 1H), 8.26 (s, 1H), 8.11(s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.75-7.68 (m, 2H),7.58 (t, 1H), 7.53 (s, 1H), 7.04-6.94 (m, 2H), 3.89 (s, 3H), 3.84 (s,3H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 445.4; Observed mass:455.7 [M+H]⁺ (rt: 0.75 min).

Example 191N-(2′-fluoro-4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamidea)5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 189(e) (2.5 g, 5.5 mmol) inethanol (50 ml) was added aqueous solution of NaOH (2 g, 50 mmol, 9 eq.)and the mixture was heated at 90° C. for 2 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was then distilled off toafford the compound in 92% yield (2.1 g).

b)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution of the compound of Example 191(a) (0.8 g, 1.94 mmol) inDCM was added pyridine (0.8 ml, 10.12 mmol) followed by cyclopropanesulfonyl chloride (0.326 g, 2.33 mmol, 1.2 eq.). The mixture was stirredfor 16 h and quenched and extracted as in Example 2(b). The solvent wasdistilled off to afford the crude residue which was purified by columnchromatography (60-120 silica gel, 4% methanol in DCM) to afford theproduct in 80% yield (0.8 g).

c)N-(2′-fluoro-4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 191(b) (150 mg,0.295 mmol) using the procedure of Example 148(f) to give the product in41% yield (45 mg). H-NMR (400 MHz, DMSO-D6) δ=8.94 (bs, 1H), 8.25 (s,1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.72-7.66 (m, 2H), 7.64-7.560 (m, 3H),7.51 (s, 1H), 7.03 (d, 1H), 6.95 (dd, 1H), 3.89 (s, 3H), 3.84 (s, 3H),2.87 (m, 1H), 1.02 (d, 4H); LC-MS (ESI); Calculated mass: 517.57:Observed mass: 518.1 [M+H]⁺ (rt: 1.39 min).

Example 192 Cyclopropanesulfonic acid{2′-fluoro-4′-methoxy-5-[5-(1H-pyrazol-4-yl)-benzoimidazol-1-yl]-biphenyl-3-yl}-amide

The compound was prepared from the compound of Example 189(e) usingprocedure of Example 2 and cyclopropane sulfonyl chloride and theprocedure of Example 148(f). ¹H-NMR (400 MHz, DMSO-D6) δ=10.22 (s, 1H),8.83 (s, 1H), 8.17 (s, 2H), 8.07 (s, 1H), 7.70 (s, 2H), 7.64-7.60 (t,1H), 7.56 (s, 2H), 7.50 (s, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 3.85 (s,3H), 2.90-2.80 (m, 1H), 1.10 (t, 3H), 1.02 (d, 4H); LC-MS (ESI):Calculated mass: 503.55; Observed mass: 503.9 [M+H]⁺ (rt: 1.24 min).

Example 193N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamidea)2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine

The compound was prepared from the compound of Example 168(e) (0.6 g,1.35 mmol) using the procedure of Example 186(a) to give the product in70% yield (0.38 g). LC-MS (ESI): Calculated mass: 401.41; Observed mass:402.1 [M+H]⁺ (rt: 1.198 min).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 193(a) (85 mg,0.211 mmol) using the procedure of Example 186(b) to give the product in35% yield (34 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H), 7.94 (s,1H), 7.79-7.69 (m, 2H), 7.51-7.49 (m, 1H), 7.42 (m, 2H), 7.34 (s, 1H),7.31 (s, 1H), 7.25 (m, 1H), 6.44 (s, 1H), 3.89 (s, 3H), 3.00 (s, 3H);LC-MS (ESI): Calculated mass: 479.5; Observed mass: 480.1 [M+H]⁺ (rt:1.34 min).

Example 194N-(5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea)N-(2′,4′-difluoro-5-((2-nitro-4-(1H-1,2,4-triazol-1-yl)phenyl)amino)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 17(c) (0.67 g, 1.31 mmol) inDMF (2 ml) were added 1,2,4-triazole (0.136 g, 1.95 mmol, 1.5 eq.),copper(I) oxide (0.188 g, 1.31 mmol, 1 eq.) and cesium carbonate (0.85g, 2.62 mmol, 2 eq.) and then the mixture was heated at 90° C. for 12 h.The mixture was quenched and extracted as in Example 1(d). The solventwas distilled off to afford the crude residue which was purified bycolumn chromatography (60-120 silica gel, 70% ethyl acetate in hexane)to give the product in 68% yield (0.4 g).

b)N-(5-((2-amino-4-(1H-1,2,4-triazol-1-yl)phenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 194(a) (0.4 g, 0.88 mmol) inacetic acid (10 ml) at 80° C. was added iron powder (0.12 g, 2.2 mmol,2.5 eq) slowly portionwise over a period of 10 min (caution: highlyexothermic reaction). After completion of the addition, the mixture washeated at 80° C. for 1 h and quenched by the addition of crushed ice.The precipitate formed was filtered and washed with cold water to obtaina solid which was dried under high vacuum to give the product in 67.5%yield (0.25 g).

c)N-(5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 194(b) (0.250 g, 0.595 mmol) andformic acid (3 ml) was heated at 80° C. for 1 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The crudematerial was purified by preparative HPLC to afford the product in 29%yield (75 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.36 (s, 1H),8.81 (s, 1H), 8.3 (s, 1H), 8.26 (s, 1H), 8.08 (m, 1H), 7.88-7.87 (m,3H), 7.8-7.7 (m, 3H), 7.55 (s, 1H), 7.5-7.4 (m, 1H), 7.32-7.24 (m, 1H),2.12 (s, 3H); LC-MS (ESI): Calculated mass: 430.41; Observed mass: 430.8[M+H]⁺ (rt: 1.17 min).

Example 195 N-(5-(5-(1H-1, 2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 194(c) (0.26 g, 0.6 mmol) inethanol (5 ml) was added 1:1 HCl solution (3 ml) and the mixture washeated at 80° C. for 1 h. The mixture was neutralised with sodiumbicarbonate solution and extracted as in Example 2(b). The solvent wasdistilled off to afford the product in 56% yield (0.13 g). LC-MS (ESI):Calculated mass: 388.37; Observed mass: 388.8 [M+H]⁺ (rt: 0.5 min).

b) N-(5-(5-(1H-1, 2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 195(a) (65 mg,0.167 mmol) using the procedure of Example 186(b) and ethanesulfonylchloride (32 mg, 0.15 mmol, 1.5 eq.) to give the product in 15% yield(12 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.50 (br s, 1H), 9.15 (m, 1H),8.85 (s, 1H), 8.30-8.25 (m, 2H), 7.83-7.76 (m, 3H), 7.60-7.48 (m, 4H),7.22 (m, 1H), 3.32 (q, 2H), 1.27-1.24 (t, 3H); LC-MS (ESI): Calculatedmass: 480.49; Observed mass: 480.8 [M+H]⁺ (rt: 1.41 min).

Example 196N-(5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 195(a) using theprocedures of Example 195. ¹H NMR (300 MHz, DMSO-d₆): δ 10.30 (br s,1H), 9.35 (m, 1H), 8.82 (s, 1H), 8.29-8.25 (m, 2H), 7.87-7.76 (m, 3H),7.61-7.46 (m, 4H), 7.27 (m, 1H), 3.18 (s, 3H); LC-MS (ESI): Calculatedmass: 466.46; Observed mass: 467.8 [M+H]⁺ (rt: 0.71 min).

Example 197N-(5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 195(a) using theprocedures of Example 195 and cyclopropane sulfonyl chloride. ¹H NMR(300 MHz, DMSO-d₆): δ 10.40 (br s, 1H), 9.45 (m, 1H), 8.80 (s, 1H),8.35-8.25 (m, 2H), 7.88-7.76 (m, 3H), 7.65-7.48 (m, 4H), 7.21 (m, 1H),2.96-2.9 (m, 1H), 1.04-1.0 (m, 4H); LC-MS (ESI): Calculated mass: 492.5;Observed mass: 493.1 [M+H]⁺ (rt: 1.43 min).

Example 198N-(5-(5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)propionamide

To a solution of the compound of Example 195(a) (50 mg, 0.128 mmol) inDMF (2 ml) was added propionic acid (14 mg, 0.192 mmol, 1.5 eq.). HATU(73 mg, 0.192 mmol, 1.5 eq.) was added and the mixture was stirred at RTfor 6 h. The mixture was quenched with chilled water and the precipitatewas collected to afford the product in 26% yield (15 mg). ¹H NMR (400MHz, CD₃OD): δ 9.17 (s, 1H), 8.67 (s, 1H), 8.24-8.22 (m, 2H), 8.17 (m,1H), 7.89 (s, 2H), 7.7-7.64 (m, 1H), 7.55 (m, 1H), 7.17-7.11 (m, 2H),2.52-2.46 (q, 2H), 1.27-1.23 (t, 3H); LC-MS (ESI): Calculated mass:444.44; Observed mass: 445.2 [M+H]⁺ (rt: 1.35 min).

Example 199N-(5-(5-(1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 17(c) using theprocedures of Example 194 and 1,2,3-triazole. ¹H NMR, 300 MHz:(DMSO-d₆): δ 10.37 (s, 1H), 8.24 (m, 3H), 8.11-8.08 (m, 3H), 7.98-7.9(m, 1H), 7.85 (s, 1H), 7.8-7.7 (m, 1H), 7.55 (m, 1H), 7.5-7.42 (m, 1H),7.32-7.24 (m, 1H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 430.41;Observed mass: 431.1 [M+H]⁺ (rt: 1.53 min).

Example 200N-(5-(5-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 1(h) (20 g, 45.2 mmol) inethanol (250 ml) was added aqueous solution of NaOH (5 g, 125 mmol, 2.75eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 99% yield (18 g).

b)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(a) (3.0 g,7.5 mmol) using the procedure of Example 186(b) and ethanesulfonylchloride (4 g, 30.7 mmol, 4 eq.) to give the product in 95% yield (3.5g).

c)N-(5-(5-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

A solution of the compound of Example 200(b) (2.5 g, 5.08 mmol) in1,2-dimethoxyethane (75 ml) was degassed by N₂ bubbling for 5 min.4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.18 g,6.1 mmol, 1.2 eq.) was added and the mixture was degassed for another 5min. Pd(PPh₃)₄ (0.28 g, 0.254 mmol, 0.05 eq.) and aqueous sodiumcarbonate (1.0 g, 9.48 mmol, 2.0 eq.) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby column chromatography (60-120 silica gel, 80% ethyl acetate inhexane) to give the product in 30% yield (0.7 g). ¹H-NMR (300 MHz,DMSO-D6) δ=8.20 (bs, 2H), 8.08 (bs, 1H), 7.75 (m, 3H), 7.62 (s, 2H),7.50 (m, 2H), 7.30 (m, 1H), 3.31 (q, 2H), 1.27 (t, 3H) LC-MS (ESI):Calculated mass: 479.5; Observed mass: 480.1 [M+H]⁺ (rt: 1.22 min).

d)N-(5-(5-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of the compound of Example 200(c) (50 mg, 0.104 mmol) inDCM was added pyridine (0.5 ml, 6.32 mmol) followed by cyclopropanesulfonyl chloride (22 mg, 0.139 mmol, 1.5 eq.). The reaction was stirredfor 1 h and quenched and extracted as in Example 2(b). The solvent wasdistilled off to afford the crude residue which was purified bypreparative HPLC to give the product in 89% yield (40 mg). ¹H-NMR (400MHz, DMSO-D6) 8=10.36 (s, 1H), 8.89 (d, 1H), 8.61 (s, 1H), 8.28 (s, 1H),7.86 (d, 1H), 7.77-7.74 (m, 2H), 7.60 (s, 2H), 7.48-7.46 (m, 2H), 7.29(t, 1H), 3.30 (q, 2H), 3.20-3.18 (m, 1H), 1.33-1.32 (m, 2H), 1.26-1.23(m, 7H) LC-MS (ESI): Calculated mass: 583.63; Observed mass: 584.1[M+H]⁺ (rt: 1.62 min).

Example 201N-(2′,4′-difluoro-5-(5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedures of Example 200(c). H-NMR (300 MHz, CD3OD) δ=9.10 (bs, 4H),8.14-8.10 (m, 1H), 7.97-7.82 (m, 1H), 7.80 (d, 1H), 7.60-7.52 (m, 3H),7.46 (s, 1H), 7.06-7.04 (m, 2H), 3.25 (m, 2H), 1.28 (t, 3H); LC-MS(ESI): Calculated mass: 419.51; Observed mass: 492.1 [M+H]⁺ (rt: 1.43min).

Example 202N-(2′,4′-difluoro-5-(5-(pyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedures of Example 200(c). H-NMR (300 MHz, CD3OD) δ=8.95 (s, 1H),8.84 (d, 2H), 8.44 (d, 3H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64-7.56 (m,1H), 7.51 (d, 2H), 7.11-7.04 (dt, 1H), 3.21 (q, 2H), 1.33 (t, 3H); LC-MS(ESI): Calculated mass: 490.52; Observed mass: 490.9 [M+H]⁺ (rt: 0.37min).

Example 203N-(5-(5-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of of Example 200(a) (15 g,37.5 mmoles) using the procedure of Example 186(b) and cyclopropanesulfonyl chloride (10 ml, 56.25 mmol, 1.5 eq.) followed by the procedureof Example 200(c) to give the product in 40% yield (36 mg). ¹H-NMR (400MHz, DMSO-D6) δ=10.33 (s, 1H), 8.88 (s, 1H), 8.20 (s, 2H), 8.09 (s, 1H),7.80-7.77 (m, 1H), 7.73 (s, 2H), 7.63 (d, 2H), 7.53 (d, 1H), 7.52-7.49(m, 1H), 7.32-7.31 (m, 1H), 1.05 (d, 5H) ppm. LC-MS (ESI): Calculatedmass: 491.51; Observed mass: 492.4 [M+H]⁺ (rt: 1.34 min).

Example 204N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 167 using theprocedures of Example 2 and cyclopropane sulfonyl chloride. H-NMR (300MHz, DMSO-D6) δ=8.64 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H),7.80-7.72 (m, 1H), 7.65 (d, 2H), 7.55-7.52 (m, 3H), 7.45 (m, 2H),7.32-7.22 (m, 1H), 4.52 (m, 1H), 2.82 (m, 1H), 1.48 (s, 3H), 1.46 (s,3H), 1.01-0.99 (m, 4H); LC-MS (ESI): Calculated mass: 533.59; Observedmass: 534.1 [M+H]⁺ (rt: 1.59 min).

Example 205N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-methoxyacetamidea)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-methoxyacetamide

To a solution of the compound of Example 200(a) (250 mg, 0.625 mmol) inDCM was added TEA (0.5 ml, 3.46 mmol, 5.5 eq.) followed by2-methoxyacetyl chloride (81 mg, 0.75 mmol, 1.2 eq.). The mixture wasstirred for 2 h and quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude residue which was purifiedby column chromatography (60-120 silica gel, 20% Ethyl acetate inhexane, 68% yield (200 mg).

b)N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-methoxyacetamide

The compound was prepared from the compound of Example 205(a) (100 mg,0.212 mmol) using the procedure of Example 200(c) and1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(70 mg, 0.297 mmol, 1.4 eq.) to give the title product in 57% yield (60mg). H-NMR (300 MHz, DMSO-D6) 8=8.64 (s, 1H), 8.30 (s, 1H), 8.01 (s,1H), 7.95 (s, 1H), 7.80-7.72 (m, 1H), 7.65 (d, 2H), 7.55-7.52 (m, 3H),7.45 (m, 2H), 7.32-7.22 (m, 1H), 4.52 (m, 1H), 2.82 (m, 1H), 1.48 (s,3H), 1.46 (s, 3H), 1.01-0.99 (m, 4H); LC-MS (ESI): Calculated mass:501.53; Observed mass: 502.1 [M+H]⁺ (rt: 1.55 min).

Example 206N-(5-(5-(1-acetyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCM(1 ml) was added TEA (0.1 ml, 0.69 mmol, 6.9 eq.) followed by acetylchloride (12 mg, 0.142 mmol, 1.4 eq.). The mixture was stirred for 2 hand quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the crude residue which was purified by preparative HPLCto yield the product in 74% yield (40 mg). H-NMR (300 MHz, DMSO-D6)δ=8.93 (bs, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.24 (s, 1H), 7.83 (d, 1H),7.76-7.70 (m, 2H), 7.58 (bs, 2H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 1H),3.15 (s, 3H), 2.90-2.80 (m, 1H), 2.67 (s, 3H), 1.01 (d, 4H); LC-MS(ESI): Calculated mass: 533.55; Observed mass: 534.1 [M+H]⁺ (rt: 1.55min).

Example 207N-(2′,4′-difluoro-5-(5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCMwas added pyridine (16 mg, 0.202 mmol, 2.0 eq.) followed bymethanesulfonyl chloride (14 mg, 0.122 mmol, 1.2 eq.). The mixture wasstirred for 1 h and quenched and extracted as in Example 2(b). Thesolvent was distilled off to afford the crude residue which was purifiedby preparative HPLC to give the product in 60% yield (40 mg). H-NMR (400MHz, DMSO-D6) δ=10.32 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H),8.29 (s, 1H), 7.88 (d, 1H), 7.76 (dd, 2H), 7.63 (d, 2H), 7.52 (s, 1H),7.50-7.47 (m, 1H), 7.30-7.29 (dt, 1H), 3.61 (s, 3H), 2.90-2.86 (m, 1H),1.04-1.02 (d, 4H); LC-MS (ESI): Calculated mass: 569.6; Observed mass:569.9 [M+H]⁺ (rt: 0.64 min).

Example 208N-(5-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamidea)N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-methanesulfonamide

To a solution of the compound was prepared from the compound of Example200(a) (3.0 g, 7.5 mmol) in DCM was added pyridine (5 ml, 63.2 mmol, 8.4eq.) followed by methanesulfonyl chloride (1.3 g, 11.25 mmol, 1.5 eq.).The mixture was stirred for 1 h and quenched and extracted as in Example2(b). The solvent was distilled off to afford the crude residue whichwas purified by preparative HPLC to give the product in 95% yield (3.5g).

b)N-(5-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the the compound of Example 208(a) (100mg, 0.209 mmol) using the procedure of Example 200(c) and1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(82 mg, 0.313 mmol, 1.5 eq.) to give the title product in 33% yield (30mg). H-NMR (300 MHz, DMSO-D6) 8=10.28 (s, 1H), 8.63 (s, 1H), 8.28 (s,1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.80-7.70 (m, 1H), 7.70-7.60 (m, 2H),7.54 (d, 2H), 7.50-7.40 (m, 2H), 7.30-7.20 (dt, 1H), 4.72-4.65 (m, 1H),3.94 (s, 1H), 3.16 (s, 3H), 2.15-2.05 (m, 2H), 2.00-1.90 (m, 2H),1.85-1.75 (m, 2H), 1.70-1.60 (m, 2H); LC-MS (ESI): Calculated mass:533.59; Observed mass: 534.3 [M+H]⁺ (rt: 1.12 min).

Example 209N-(2′,6′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamidea)N-(5-((5-bromo-3-nitropyridin-2-yl)amino)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A solution of N-(5-amino-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(1.4 g, 6.1 mmol), 5-bromo-2-chloro-3-nitropyridine (1.6 g, 6.1 mmol,1.0 eq.) and potassium fluoride (0.53 g, 9.0 mmol, 1.5 eq.) in DMF (8ml) was heated at 110° C. for 4 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe crude product which was purified by column chromatography (60-120silica gel, 30% Ethyl acetate in hexane) to give the title product in28% yield (0.8 g).

b)N-(5-((5-bromo-3-nitropyridin-2-yl)amino)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 209(a) (0.8 g, 1.73 mmol) inTHF (25 ml) and methanol (5 ml) were added a solution of ammoniumchloride (0.37 g, 6.92 mmol, 4 eq.) in water (5 ml) and zinc (0.45 g,6.92 mmol, 4 eq). The mixture was stirred at RT for 1 h and filtered.The filtrate was diluted with water and extracted as in Example 1(d).The solvent was distilled off to afford the product in 80% yield (0.6g).

c)N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 209(b) (0.6 g, 1.38 mmol) andformic acid (3 ml) was heated at 80° C. for 1 h. Formic acid was thendistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off and hexane washings were givento the crude material to afford the title product in 98% yield (0.5 g).

d)N-(2′,6′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the the compound of Example 209(c) (1.3g, 2.94 mmol) using the procedure of Example 200(c) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.91 g, 4.41 mmol, 1.5 eq.) to give the title product in 61% yield (0.8g).

e)2′,6′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 209(d) (0.8 g, 1.8 mmol) inethanol (10 ml) was added aqueous solution of NaOH (0.2 g, 5.4 mmol, 3eq.) and the mixture was heated at 80° C. for 12 h. The mixture wasquenched with water when solid precipitated. This was purified usingbasic alumina column chromatography using 2% methanol in chloroform aseluant to give the product in 20% yield (0.15 g).

f)N-(2′,6′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamide

To a solution of the compound of Example 209(e) (15 mg, 0.37 mmol) inDMF (2 ml) was added cyclopropane carboxylic acid (40 mg, 0.55 mmol).HATU (200 mg, 0.55 mmol) was added and stirred at RT for 4 h. Themixture was quenched with chilled water and the precipitate wascollected and purified by preparative HPLC to afford the title productin 10% yield (17 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.7 (s, 1H), 8.89(s, 1H), 8.73-8.72 (d, 1H), 8.42 (d, 1H), 8.35-8.34 (t, 1H), 8.31 (s,1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.57-7.51 (m 1H),7.31-7.27 (t, 2H), 3.89 (s, 3H), 1.86-1.83 (m, 1H), 0.85-0.84 (d, 4H);LC-MS (ESI): Calculated mass: 470.47; Observed mass: 471.2 [M+H]⁺ (rt:1.43 min).

Example 2103-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuricdiamide a)3-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuric diamide

To a solution of the compound of Example 200(a) (4.0 g, 10.0 mmol) inDCM (50 ml) was added pyridine (5 ml, 63.29 mmol, 6.3 eq.) followed bydimethylsulfamoyl chloride (2.0 g, 14.0 mmol, 1.4 eq.). The mixture wasstirred for 16 h and quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude product which was purifiedby column chromatography (60-120 silica gel, 2% methanol in DCM) to givethe desired title product in 81% yield (4.1 g).

b)3-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuricdiamide

The compound was prepared from the compound of Example 210(a) (200 mg,0.394 mmol) using the procedure of Example 200(c) and1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(121 mg, 0.383 mmol, 1.3 eq.) to give the title product in 23% yield (50mg). H-NMR (300 MHz, DMSO-D6) δ=10.45 (s, 1H), 8.95 (s, 1H), 8.35 (s,1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.78-7.68 (m, 3H), 7.57 (s, 2H), 7.47(m, 2H), 7.34-7.24 (dt, 1H), 2.80 (s, 6H), 1.47 (d, 6H); LC-MS (ESI);Calculated mass: 536.6: Observed mass: 537.1 [M+H]⁺ (rt: 1.57 min).

Example 2113-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuricdiamide

The compound was prepared from the compound of Example 210(a) using theprocedures of Example 200(c) and2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.¹H NMR (300 MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H),7.99 (s, 1H), 7.95 (s, 1H), 7.75-7.56 (m, 5H), 7.48-7.43 (m, 2H), 7.27(m, 1H), 3.88 (s, 3H), 3.48-3.44 (m, 1H), 1.3 (d, 6H); LC-MS (ESI):Calculated mass: 611.66; Observed mass: 612.1 [M+H]⁺ (rt: 1.87 min).

Example 2123-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuricdiamide

To a solution of the compound of Example 211 (250 mg, 0.391 mmoles) in1,4-dioxane (10 ml), TFA (0.2 ml) was added and heated to 70° C. for 2h. The reaction mass was completely concentrated and the crude materialwas purified by preparative HPLC to give the title product in 70% yield(80 mg)¹H-NMR (300 MHz, DMSO-D6) 8=8.96 (s, 1H), 8.02 (s, 1H), 7.80 (dd,1H), 7.82 (d, 1H), 7.80-7.70 (m, 2H), 7.70-7.62 (d, 1H), 7.57 (s, 2H),7.51-7.44 (m, 2H), 7.29 (dt, 1H), 6.47 (d, 1H), 2.80 (s, 6H); LC-MS(ESI): Calculated mass: 521.54; Observed mass: 522.2 [M+H]⁺ (rt: 0.87min).

Example 213N-(5-(6-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea)N-(5-(6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared fromN-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide(2.1 g, 4.74 mmol) using the procedure of Example 200(c) to give thedesired title product in 95% yield (1.9 g).

b)N-(5-(6-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 213(a) (50 mg,0.125 mmol) using the procedure of Example 200(d) to give the product in33% yield (20 mg). H-NMR (400 MHz, CD3OD) δ=8.80 (dd, 2H), 8.73 (s, 1H),8.44 (d, 1H), 8.40 (s, 1H), 8.27 (t, 1H), 7.81 (d, 1H), 7.76 (s, 1H),7.66-7.64 (m, 1H), 7.14-7.09 (m, 2H), 3.03-2.99 (m, 1H), 2.20 (s, 3H),1.47-1.44 (m, 2H), 1.25-1.23 (m, 2H) ppm: Calculated mass: 534.54;Observed mass: 534.8 [M+H]⁺ (rt: 1.55 min).

Example 214N-(2′,4′-difluoro-5-(6-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 213(a) using theprocedures of Example 200(d). H-NMR (400 MHz, DMSO-D6+D20) 6=9.01 (s,1H), 8.99 (s, 1H), 8.92 (d, 1H), 8.69-8.68 (m, 2H), 8.31 (t, 1H), 7.90(m, 1H), 7.73 (m, 2H), 7.46 (dt, 1H), 7.29 (dt, 1H), 3.63 (s, 3H), 2.14(s, 3H); LC-MS (ESI): Calculated mass: 508.5; Observed mass: 508.7[M+H]⁺ (rt: 1.46 min).

Example 215N-(5-(6-(1-(ethylsulfonyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 213(a) using theprocedures of Example 200(d). ¹H-NMR (400 MHz, DMSO-D6) G=10.41 (s, 1H),9.03 (s, 1H), 8.98 (s, 1H), 8.92 (d, 1H), 8.69 (s, 1H), 8.31 (s, 1H),7.88 (s, 1H), 7.71 (m, 2H), 7.47 (dt, 1H), 7.28 (dt, 1H), 3.77 (q, 2H),1.16 (t, 3H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 522.53;Observed mass: 523.2 [M+H]⁺ (rt: 1.56 min).

Example 216 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-N,N-dimethylsulfuric diamide a)N-(2′, 4′-difluoro-5-((6-bromo)-3H-imidazo[4, 5-b] pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-N,N-dimethylsulfuric diamide

To a solution of N-(2′,4′-difluoro-5-((6-bromo)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)amine (3.0 g, 7.48 mmol) in DCM (10ml) was added pyridine (3 ml, 37.9 mmol, 2 eq.) followed bydimethylsulfamoyl chloride (1.6 g, 11.22 mmol, 1.5 eq.). The mixture wasstirred for 16 h and quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude product which was purifiedby preparative HPLC to give the title product in 55% yield (2.1 g).

b) N-(2′, 4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-N,N-dimethylsulfuric diamide

The compound was prepared from the compound of Example 216(a) (150 mg,0.295 mmol) using the procedure of Example 200(c) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole togive the title product in 41% yield (45 mg). ¹H NMR (300 MHz, DMSO-d₆):δ=8.95 (s, 1H), 8.72 (s, 1H), 7.41 (d, 1H), 8.32 (s, 1H), 8.05 (s, 1H),7.98 (m, 1H), 7.72 (m, 1H), 7.50-7.42 (m, 2H), 7.32-7.24 (m, 2H), 3.90(s, 3H), 2.81 (s, 6H); LC-MS (ESI); Calculated mass: 509.53: Observedmass: 510.1 [M+H]⁺ (rt: 1.49 min).

Example 217N-(2′,4′-difluoro-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-N,N-dimethylsulfuric diamide

The compound was prepared from the compound of Example 216(a) using theprocedures of Example 200(c) and1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.¹H-NMR (300 MHz, DMSO-D6) δ=10.40 (s, 1H), 8.94 (s, 1H), 8.75 (d, 1H),8.40 (m, 2H), 8.06 (s, 1H), 7.99 (t, 1H), 7.76-7.68 (m, 2H), 7.50-7.40(m, 2H), 7.32-7.24 (dt, 1H), 4.60-4.50 (m, 1H), 2.81 (s, 6H), 1.48 (s,6H); LC-MS (ESI): Calculated mass: 537.58; Observed mass: 538.1 [M+H]⁺(rt: 1.62 min).

Example 218N-(2′,4′-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuric diamide a)N-(2′, 4′-difluoro-5-(6-(benzyloxy)pyridin-3-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-N,N′-dimethylsulfuric diamide

A solution of the compound of Example 216(a) (300 mg, 0.59 mmol) in1,2-dimethoxyethane (10 ml) was degassed by N₂ bubbling for 5 min.2-(Benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(220 mg, 0.708 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd(PPh₃)₄ (34 mg, 0.0295 mmol, 0.05 eq.) and aqueoussodium carbonate (125 mg, 1.179 mmol, 2.0 eq.) were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to give the title product in 69% yield(250 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.03 (s, 1H), 8.78(s, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.25-8.2 (m, 1H), 7.98 (s, 1H),7.74 (m, 2H), 7.7-7.5 (m, 2H), 7.5-7.25 (m, 1H), 7.08-7.0 (d, 1H), 5.43(s, 2H), 2.81 (s, 6H); LC-MS (ESI); Calculated mass: 614.2: Observedmass: 613.2 [M−H]⁺ (rt: 1.4 min).

b)N-(2′,4′-difluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-N,N-dimethylsulfuricdiamide

To a solution of the compound of Example 218(a) (240 mg, 0.391 mmoles)in 1,4-dioxane (10 ml), TFA (0.8 ml) was added and heated to 70° C. for2 h. The reaction mass was completely concentrated and the crudematerial was purified by preparative HPLC to give the title product in50% yield (80 mg). H-NMR (300 MHz, DMSO-D6) δ=10.40 (s, 1H), 8.99 (s,1H), 8.67 (d, 1H), 8.42 (d, 1H), 8.00-7.95 (m, 2H), 7.88 (s, 1H), 7.73(m, 2H), 7.50-7.43 (m, 2H), 7.32-7.26 (dt, 1H), 6.48 (d, 1H), 2.81 (s,6H); LC-MS (ESI); Calculated mass: 522.53: Observed mass: 523.1 [M+H]⁺(rt: 1.39 min).

Example 219N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) (0.2 g,0.452 mmol) using the procedure of Example 200(c) and2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-olto give the title product in 55.79% yield (0.13 g). ¹H NMR (300 MHz,DMSO-d6): δ 10.42 (s, 1H), 8.96 (s, 1H), 8.11 (s, 1H), 8.01 (s, 2H),7.82 (s, 1H), 7.71 (m, 3H), 7.54-7.41 (m, 2H), 7.29-7.25 (m, 1H),4.24-4.18 (t, 2H), 2.155 (s, 3H), 1.98-1.92 (s, 2H), Calculated mass:515.55; Observed mass: 516.3 [M+H]⁺ (rt: 1.2 min).

Example 220N-(4′-fluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared fromN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide(0.07 g, 0.164 mmol) using the procedure of Example 200(c) and2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol(0.092 g, 0.329 mmol, 2.0 eq.) to give the title product in 22.2% yield(0.018 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.68 (s, 1H),8.25 (s, 1H), 7.99 (d, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.69 (m, 2H),7.65 (m, 1H), 7.61 (m, 2H), 7.36 (t, 2H), 4.48 (s, 1H); 4.26 (m, 2H);2.12 (s, 3H); 1.91 (m, 2H); 1.15 (s, 6H); LC-MS (ESI): Calculated mass:497.56 Observed mass: 497.9 [M+H]⁺ (rt: 0.9 min).

Example 221 N-(2′,4′-difluoro-5-(5-(3-fluoropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 200(c). ¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s,1H), 8.85 (s, 1H), 8.70 (s, 1H), 8.541-8.53 (d, 1H), 8.14-8.11 (d, 2H),7.88-7.84 (m, 2H), 7.79-7.69 (m, 3H), 7.56 (s, 1H), 7.48-7.46 (t, 1H),2.155 (s, 3H), 2.12 (s, 3H), Calculated mass: 458.43; Observed mass:459.2[M+H]⁺ (rt: 1.55 min).

Example 222 N-(2′,4′-difluoro-5-(5-(3-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl) acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 220. ¹H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H)8.80 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.97-7.91 (d,1H), 7.90-7.76 (m, 3H), 7.56 (d, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 2.25(s, 3H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 443.45; Observedmass: 444.2 [M+H]⁺ (rt: 0.69 min).

Example 223 Ethyl 3-((2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl) amino)-3-oxopropanoate

To a solution of the compound of Example 2(a) (80 mg, 0.1995 mmol) inDCM was added TEA (40 mg, 0.399 mmol, 2.0 eq.) followed by ethyl3-chloro-3-oxopropanoate (32.9 mg, 0.219 mmol, 1.1 eq). The mixture wasstirred for 2 h and quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude residue which was purifiedby preparative HPLC to give the pure product in 20% yield (20 mg) ¹H NMR(400 MHz, DMSO-d₆): δ 10.7 (s, 1H), 8.77 (s, 1H), 8.23 (s, 1H), 8.10 (s,1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.78 (d, 1H), 7.73 (d,1H), 7.65 (d, 1H), 7.59 (s, 1H), 7.49 (t, 1H), 7.3 (t, 1H), 3.90 (s,3H), 3.82 (q, 2H), 1.4 (t, 3H), 3.45 (s, 2H); LC-MS (ESI): Calculatedmass: 515.51; Observed mass: 516.4 [M+H]⁺ (rt: 0.96 min).

Example 224 3-((2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl) amino)-3-oxopropanoic acid

To a solution of the compound of Example 223 (20 mg, 0.0388 mmol) in THF(10 ml) was added aqueous solution of lithium hydroxide (4 mg, 0.0776mmol, 2 eq) and the mixture was stirred at RT for 2 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the crude residue which was purified by preparative HPLC togive the pure product in 90% yield (25 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.7 (s, 1H), 8.77 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H),7.97 (s, 1H), 7.83 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.65 (d, 1H),7.59 (s, 1H), 7.49 (t, 1H), 7.3 (t, 1H), 3.90 (s, 3H), 3.45 (s, 2H);LC-MS (ESI): Calculated mass: 487.15; Observed mass: 488.0 [M+H]⁺ (rt:0.638 min).

Example 225N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide

To a solution of the compound of Example 2(a) (100 mg, 0.249 mmol) inDMF was added 2-(1H-1,2,4-triazol-1-yl)acetic acid (47 mg, 0.374, mmol,1.5 eq.) followed by HATU (189 mg, 0.498 mmol, 2.0 eq) and DIPEA (96.5mg, 0.74 mmol, 3.0 eq). The mixture was stirred for 16 h and quenchedand extracted as in Example 1(d). The solvent was distilled off toafford the crude residue which was purified by preparative HPLC to givethe product in 71.4% yield (90 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.9(s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 8.02(s, 1H), 8.00 (d, 1H), 7.93 (s, 1H), 7.80-7.75 (m, 2H), 7.7 (d, 1H),7.61-7.59 (m, 2H), 7.48-7.42 (m, 1H), 7.3 (m, 1H) 4.12 (s, 1H), 3.87 (s,3H); LC-MS (ESI): Calculated mass: 510.17; Observed mass: 511.2 [M+H]⁺(rt: 0.386 min).

Example 226 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(2H-tetrazol-5-yl) acetamide a) 2-Cyano-N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl) acetamide

To a solution of the compound of Example 2(a) (100 mg, 0.249 mmol) inDMF was added cyanoacetic acid (25.6 mg, 0.299 mmol, 1.2 eq) followed byHATU (184 mg, 0.485 mmol, 2.0 eq) and DIPEA (0.15 ml, 0.74 mmol, 3.0eq). The mixture was stirred for 16 h and quenched and extracted as inExample 1(d). The solvent was distilled off to afford the crude residuewhich was purified by column chromatography to give the product in 19%yield (80 mg). LC-MS (ESI): Calculated mass: 468; Observed mass: 469.3[M+H]⁺ (rt: 0.88 min).

b) N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(2H-tetrazol-5-yl) acetamide

To a solution of the compound of Example 226(a) (80 mg, 0.170 mmol) inDMF was added sodium azide (11 mg, 0.170 mmol, 1. eq) followed byammonium chloride (10 mg, 0.188 mmol, 1.1 eq). The mixture was stirredat 80° C. for 16 h and quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude residue which was purifiedby preparative HPLC to give the product in 6.8% yield (6 mg). ¹H NMR(400 MHz, CD₃OD): δ 8.51 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.92 (s,1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.73-7.60 (m, 3H), 7.53 (s, 1H),7.16-7.10 (m, 2H), 4.12 (s, 2H), 3.96 (s, 3H); LC-MS (ESI): Calculatedmass: 511.17; Observed mass: 512.1 [M+H]⁺ (rt: 0.874 min).

Example 227(3S,5R)—N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3,5-dimethylpiperazine-1-carboxamide

To a solution of the compound of Example 2(a) (80 mg, 0.2 mmol) in DCMwas added 20% phosgene in toluene (0.2 ml, 0.4 mmol, 2 eq.) at 0° C. Themixture was stirred for 1 h and excess phosgene was removed by purgingwith nitrogen, followed by the addition of 2,6-dimethylpiperazine (34mg, 0.3 mmol, 1.5 eq.). The mixture was stirred overnight and quenchedand extracted as in Example 1(d). The solvent was distilled off toafford the crude residue which was purified by preparative HPLC to givethe pure product in 7% yield (7 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.48 (s,1H), 8.0 (s, 1H), 7.9 (s, 1H), 7.86-7.85 (m, 2H), 7.72-7.65 (d, 1H),7.65-7.59 (m, 4H), 7.43 (s, 1H), 7.11 (m, 1H), 4.2 (d, 2H), 3.1-3.0 (br,2H), 2.7-2.6 (t, 1H), 1.23-1.17 (d, 6H); LC-MS (ESI): Calculated mass:541.59; Observed mass: 542.2 [M+H]⁺ (rt: 0.632 min).

Example 228N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-4-methylpiperazine-1-carboxamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 227. ¹H NMR (300 MHz, CD₃OD): δ 8.48 (s, 1H), 8.0(s, 1H), 7.9 (s, 1H), 7.86-7.85 (m, 2H), 7.72-7.65 (d, 1H), 7.65-7.59(m, 4H), 7.43 (s, 1H), 7.11-7.09 (m, 2H), 3.94 (s, 3H), 3.63-3.60 (m,4H), 2.55-2.53 (m, 4H), 2.36 (s, 3H); LC-MS (ESI): Calculated mass:527.57; Observed mass: 528.1 [M+H]⁺ (rt: 0.632 min).

Example 229N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-((3S,5R)-3,5-dimethylpiperazin-1-yl)acetamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 226. ¹H NMR (300 MHz, DMSO-d₆): δ 8.4 (br s, 1H),8.14 (m, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.83 (m, 1H),7.72-7.70 (d, 1H), 7.66-7.59 (m, 2H), 7.55 (s, 1H), 7.15-7.11 (m, 2H),3.94 (s, 3H), 3.37 (s, 2H), 2.269 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H);LC-MS (ESI): Calculated mass: 555.62; Observed mass: 556.2 [M+H]⁺ (rt:0.75 min).

Example 2301-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 2(a) (20 mg, 0.049 mmol) in DCMwas added furfuryl isocyanate (7 mg, 0.059 mmol, 1.2 eq.) followed byDIPEA (0.01 ml, 0.0747 mmol, 1.5 eq.). The mixture was stirred overnightand quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the crude residue which was purified by preparative HPLCto give the product in 92% yield (24 mg). ¹H NMR (400 MHz, DMSO-d₆): δ9.07 (s, 1H), 8.95 (brS, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.97-7.96 (m,2H), 7.75-7.59 (m, 5H), 7.40 (m, 2H), 7.26 (m, 1H), 6.82 (t, 1H), 6.4(m, 1H), 6.27 (m, 1H), 4.32-4.31 (d, 2H), 3.88 (s, 3H); LC-MS (ESI):Calculated mass: 524.52; Observed mass: 525.1 [M+H]⁺ (rt: 0.75 min).

Example 231N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(piperazin-1-yl)acetamidea) tert-butyl4-(2-((2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

To a solution of the compound of Example 2(a) (100 mg, 0.249 mmol) inDMF was added 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (121mg, 0.498 mmol, 2 eq.) followed by HATU (190 mg, 0.498 mmol, 2 eq.) andDIPEA (0.17 ml, 0.996 mmol, 4 eq.). The mixture was stirred for 16 h andquenched and extracted as in Example 1(d). The solvent was distilled offto give the crude residue which was purified by preparative HPLC to givethe product in 25% yield (25 mg).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(piperazin-1-yl)acetamide

To a solution of the compound of Example 231(a) (23 mg, 0.038 mmol) inDCM (1 ml) at 0° C. was added TFA (1 ml) and the mixture was stirred atRT overnight. The solvent was distilled off to afford the crude residuewhich was recrystallized from diethyl ether to give the product in 70%yield (18 mg). ¹H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.75 (s, 1H),8.62 (br s, 2H), 8.21 (s, 1H), 8.14 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H),7.9 (s, 1H), 7.75-7.7 (m, 2H), 7.63-7.58 (m, 2H), 7.48-7.44 (t, 1H),7.3-7.26 (t, 1H); LC-MS (ESI): Calculated mass: 527.22; Observed mass:528.1 [M+H]⁺ (rt: 0.632 min).

Example 232Methyl(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)carbamate

To a solution of the compound of Example 2(a) (60 mg, 0.15 mmol) inchloroform (5 ml) at 0° C. were added methyl chloroformate (14 mg, 0.15mmol, 1 eq.) and pyridine (0.024 ml, 0.3 mmol, 2 eq.). The mixture wasstirred at RT for 1 h and then quenched with water and extracted withchloroform (3×50 ml). The combined organic layer was washed with water,brine and dried over sodium sulphate. The solvent was distilled off toafford the title compound in 37% yield (25 mg). ¹H NMR (300 MHz,DMSO-d₆): δ 10.13 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.98-7.92 (m,3H), 7.70-7.67 (m, 3H), 7.60 (m, 1H), 7.46 (m, 2H), 7.27 (m, 1H), 3.87(m, 3H), 3.72 (s, 3H); LC-MS (ESI): Calculated mass: 459.15; Observedmass: 460.2 [M+H]⁺ (rt: 0.94 min).

Example 233 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-morpholinoacetamide

The compound was prepared from the compound of Example 2(a) (100 mg,0.249 mmol) using the procedure of Example 225 and 2-morpholinoaceticacid (54 mg, 0.373, mmol, 1.5 eq.) to give the product in 19% yield (25mg). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.91 (s, 1H), 8.20 (s,1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.77-7.71(m, 2H), 7.66-7.64 (m, 2H), 7.46-7.40 (m, 1H), 7.29-7.25 (m, 1H); 4.25(s, 2H), 3.9 (s, 3H), 3.87-3.15 (m, 8H); LC-MS (ESI): Calculated mass:528.55 Observed mass: 529.3 [M+H]⁺ (rt: 0.38 min).

Example 234N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(piperidin-1-yl)acetamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H),8.18 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H),7.75-7.70 (m, 2H), 7.67-7.63 (m, 2H), 7.42-7.37 (t, 1H), 7.27-7.23 (t,1H), 4.12 (s, 2H), 3.86 (s, 3H), 3.50-3.35 (m, 2H), 3.05-2.99 (t, 2H),1.79-1.68 (m, 5H), 1.40 (s, 1H); LC-MS (ESI): Calculated mass: 526.58;Observed mass: 527.1 [M+H]⁺ (rt: 0.36 min).

Example 235 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(pyrrolidin-1-yl) acetamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 11.02 (s, 1H),10.31 (s, 1H), 8.80 (s, 1H), 8.22. (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H),7.96 (s, 1H), 7.79-7.73 (m, 2H), 7.70 (d, 1H), 7.63-7.61 (m, 2H),7.49-7.47 (t, 1H), 7.31-7.29 (t, 1H), 4.34-4.32 (d, 2H), 3.88 (s, 3H),3.16 (m, 1H), 2.03-1.91 (m, 4H); Calculated mass: 512.55; Observed mass:513.5 [M+H]⁺ (rt: 0.28 min).

Example 236 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,3′-dihydro-[1,1′biphenyl]-3-yl)-4-ethylpiperazine-1-carboxamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 227. NMR (400 MHz, DMSO-D6): δ 9.53 (brs, 1H), 9.22(s, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 7.98 (t, 2H). 7.77-7.72 (m, 3H),7.63 (dd, 1H), 7.49-7.44 (m, 2H), 7.283 (dt, 1H), 4.35 (d, 2H), 3.89 (s,3H), 3.57 (d, 3H), 3.24-3.18 (m, 3H), 3.07-3.02 (m, 2H), 1.26 (t, 3H):LC-MS (ESI): Calculated mass: 543.6; Observed mass: 543.2 M+H]⁺ (rt:0.224 min).

Example 237N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-(pyrrolidin-1-yl)acetamide

The compound was prepared from the compound of Example 132(a) (100 mg,0.248 mmol) using the procedure of Example 225 and2-(pyrrolidin-1-yl)acetic acid (35 mg, 0.273 mmol, 1.1 eq) to give theproduct in 7.08% yield (9 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s,1H), 8.6 (s, 1H), 8.29 (s, 2H), 8.10 (s, 1H), 7.93 (s, 1H), 7.85 (s,1H), 7.78 (s, 1H), 7.67-7.61 (m, 1H), 7.14-7.08 (m, 2H), 4.29 (s, 2H),3.95 (s, 3H), 3.80 (s, 2H), 3.29 (t, 2H), 2.14 (t, 4H); LC-MS (ESI):Calculated mass: 513.21; Observed mass: 514.4 [M+H]⁺ (rt: 0.27 min).

Example 238N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-morpholinoacetamide

The compound was prepared from the compound of Example 132(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 11.1 (s, 1H),8.99 (s, 1H), 8.70 (s, 1H), 8.42 (d, 2H), 8.31 (s, 1H), 8.05 (s, 1H),7.90 (s, 1H), 7.83 (s, 1H), 7.77-7.75 (m, 1H), 7.47 (t, 1H), 7.30 (t,1H), 4.27 (s, 2H), 3.90 (s, 3H), 3.82 (t, 4H), 2.50 (t, 4H); LC-MS(ESI): Calculated mass: 529.20; Observed mass: 530.4 [M+H]⁺ (rt: 0.23min).

Example 239N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-(piperidin-1-yl)acetamide

The compound was prepared from the compound of Example 132(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 11.0 (s, 1H),9.73 (s, 1H), 8.99 (s, 1H), 8.70 (d, 1H), 8.43 (t, 2H), 8.31 (s, 1H),8.05 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.79-7.73 (m, 1H), 7.49-7.44(m, 1H), 7.30 (t, 1H), 4.20 (s, 2H), 3.90 (s, 3H), 3.37 (t, 4H),1.80-1.69 (m, 6H); LC-MS (ESI): Calculated mass: 527.57; Observed mass:528.6 [M+H]⁺ (rt: 0.32 min).

Example 240 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl) piperidine-4-carboxamide a)tert-butyl 4-((2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl) carbamoyl) piperidine-1-carboxylate

The compound was prepared from the compound of Example 132(a) (100 mg,0.248 mmol) using the procedure of Example 225 and1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (56 mg, 0.248 mmol,2 eq) to give the product in 26.3% yield (40 mg). LC-MS (ESI):Calculated mass: 513.21; Observed mass: 514.4 [M+H]⁺ (rt: 0.68 min).

b) N-(2′, 4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl) piperidine-4-carboxamide

To a solution of the compound of Example 240(a) (30 mg, 0.0489 mmol) inDCM was added TFA (1 ml) and stirred at RT for 16 h. The mixture wasconcentrated to give the product in 98% yield (25 mg). ¹H NMR (400 MHz,DMSO-d₆): δ 10.50 (s, 1H), 8.94 (s, 1H), 8.72-8.66 (m, 2H), 8.40-8.35(m, 3H), 8.29 (s, 1H), 8.03 (s, 1H), 7.90-7.89 (d, 1H), 7.73-7.67 (m,2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 3.88 (s, 3H), 3.37-3.34 (d,2H), 2.99-2.90 (m, 2H), 2.73-2.68 (m, 1H), 2.01-1.98 (d, 2H), 1.85-1.77(m, 2H); LC-MS (ESI): Calculated mass: 513.21; Observed mass: 514.4[M+H]⁺ (rt: 0.68 min).

Example 241 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(1H-1, 2, 4-triazol-1-yl) acetamide

The compound was prepared from the compound of Example 132(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 10.9 (s, 1H), 9.0(s, 1H), 8.73 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 8.4 (d, 1H), 8.03 (d,1H), 7.87 (s, 1H), 7.75 (m, 1H), 7.48 (m, 1H), 7.29 (m, 1H), 5.23 (s,1H), 3.95 (s, 3H); LC-MS (ESI): Calculated mass: 511.49; Observed mass:512.1 [M+H]⁺ (rt: 1.01 min).

Example 242 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-3,5-dimethylpiperazine-1-carboxamide

To a solution of the compound of Example 132(a) (100 mg, 0.248 mmol) inDCM was added 20% phosgene (73.4 mg, 0.748 mmol, 3 eq) followed by1-ethylpiperazine (28.3 mg, 0.248 mmol, 1 eq.). The mixture was stirredfor 16 h and quenched and extracted as in Example 2(b). The solvent wasdistilled off to afford the crude residue which was purified bypreparative HPLC to give the product in 5.9% yield (8 mg). ¹H NMR (400MHz, DMSO-d₆): δ 9.13 (s, 2H), 8.90 (1, 1H), 8.70-8.69 (d, 1H),8.40-8.39 (d, 1H), 8.29 (s, 1H), 8.18 (t, 1H), 8.03 (s, 1H), 7.74-7.63(m, 3H), 7.46-7.40 (m, 1H), 7.28-7.22 (m 1H), 4.32-4.29 (d, 2H), 3.88(s, 3H), 3.34 (m, 2H), 2.80 (t, 2H), 1.24 (s, 3H), 1.22 (s, 3H); LC-MS(ESI): Calculated mass: 542.24; Observed mass: 543.3 [M+H]⁺ (rt: 0.67min).

Example 243 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl) acryl amide

To a solution of the compound of Example 132(a) (60 mg, 0.1492 mmol) inDCM was added TEA (30 mg, 0.298 mmol, 2.0 eq) followed by acryloylchloride (16.1 mg, 0.179 mmol, 1.2 eq). The mixture was stirred for 4 hand quenched and extracted as in Example 2(b). The solvent was distilledoff to afford the crude residue which was purified by preparative HPLCto give the product in 41% yield (28 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.7 (s, 1H), 8.97 (s, 1H), 8.754 (d, 1H), 8.44 (t, 1H), 8.33 (s, 1H),8.069 (d, 2H), 7.79-7.75 (m, 2H), 7.48 (t, 1H), 7.30 (t, 1H), 6.55-6.51(m, 1H), 6.32 (d, 1H), 5.84 (d, 1H), 3.92 (s, 3H); LC-MS (ESI):Calculated mass: 456.15; Observed mass: 457.1 [M+H]⁺ (rt: 1.456 min).

Example 244N-cyclopropyl-N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-sulfuric diamide

To a solution of the compound of Example 132(a) (60 mg, 0.149 mmol) inpyridine was added N-cyclopropyl-2-oxooxazolidine-3-sulfonamide (49 mg,0.238 mmol, 1.6 eq). The mixture was stirred at 50° C. for 16 h, andquenched and extracted as in Example 1(d). The solvent was distilled offto afford the crude residue which was purified by preparative HPLC togive the product in 19.4% yield (15 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.89(s, 1H), 8.71 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.77(t, 1H), 7.71 (d, 1H), 7.71-7.63 (m, 1H), 7.47 (t, 1H), 7.15-7.09 (m,2H), 3.98 (s, 3H), 2.48-2.44 (m, 1H), 0.65-0.55 (m, 4H); LC-MS (ESI):Calculated mass: 521.14; Observed mass: 522.1 [M+H]⁺ (rt: 1.480 min).

Example 245N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-N′-(furan-2-ylmethyl)sulfuricdiamide

To a solution of the compound of Example 132(a) (100 mg, 0.248 mmol) inpyridine was added N-(furan-2-ylmethyl)-2-oxooxazolidine-3-sulfonamide(97 mg, 0.398 mmol, 1.6 eq). The mixture was stirred at 50° C. for 16 h,and quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the crude residue which was purified by preparative HPLCto give the product in 18% yield (25 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.24 (s, 1H), 8.89 (s, 1H), 8.70 (d, 1H), 8.40 (d, 1H), 8.31-8.28 (m,2H), 8.03 (d, 1H), 7.71-7.64 (m, 3H), 7.46-7.43 (m, 2H), 7.32 (d, 1H),7.29-7.24 (m, 1H), 6.28-6.27 (m, 1H), 6.23 (d 1H), 4.10-4.09 (d, 2H),3.88 (s, 3H); LC-MS (ESI): Calculated mass: 561.14; Observed mass: 562.1[M+H]⁺ (rt: 1.513 min).

Example 246N-(5-(6-(2-aminopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea) tert-butyl(4-(3-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo-[4,5-b]pyridin-6-yl)pyridin-2-yl)carbamate

The compound was prepared from compound of Example 131(c) using theprocedure of Example 131(d).

b) N-(5-(6-(2-aminopyridin-4-yl)-3H-imidazo[4, 5-b] pyridin-3-yl)-2′,4′-difluoro-[1, 1′-biphenyl]-3-yl) acetamide

To a solution of the compound of Example 246(a) (0.2 g, 0.359 mmol) inDCM (5 ml) was added (1.2 ml) of TFA at 0° C. The mixture was stirred atRT for 16 h. The mixture was concentrated on vacuo, quenched withsodiumbicarbonate and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 17.7% yield (0.29 g). ¹H NMR (400MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.09 (s, 1H), 8.87 (d, 1H), 8.70-8.69.(d, 2H), 8.34 (s, 1H), 8.10-8.08 (d, 1H), 8.12 (s, 1H), 7.86 (s, 1H),7.71 (m, 2H), 7.52 (m, 1H), 7.41-7.39 (d, 1H), 7.31 (m, 2H), 2.12 (s,3H); Calculated mass: 456.48; Observed mass: 457.3 [M+H]⁺ (rt: 0.19min).

Example 247N-(2′,4′-difluoro-5-(6-(thiazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 131(c) (100 mg,0.225 mmol) in THF (6 ml) using the procedure of Example 200(c) andthiazol-2-ylzinc (II) bromide (155 m g, 0.677 mmol, 3.0 eq.) to give theproduct in 25% yield (25 mg). ¹H NMR (400 MHz, DMSO-D6): δ 10.42 (s,1H), 9.08 (d, 2H), 8.72 (d, 1H), 8.30 (s, 1H), 8.01 (d, 1H), 7.93 (s,1H), 7.90 (d, 1H), 7.75-7.72 (m, 2H), 7.46 (t, 1H), 7.28 (t, 1H), 2.13(s, 3H); LC-MS (ESI): Calculated mass: 447.46; Observed mass: 448.0[M+H]⁺

Example 248N-(5-(6-(6-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 131(c) using theprocedure of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H),9.02 (s, 1H), 8.76 (d, 1H), 8.55 (d, 1H), 8.44-8.34 (m, 3H), 8.04 (br s,2H), 7.84 (s, 1H), 7.75-7.67 (m, 2H), 7.49-7.42 (m, 1H), 7.30-7.25 (m,1H), 7.10-7.07 (m, 1H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass:456.15; Observed mass: 457.2 [M+H]⁺ (rt: 0.20 min).

Example 249N-(5-(5-(4-aminophenyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 131(c) using theprocedure of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H),8.98 (s, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H),7.71-7.68 (m, 1H), 7.62-7.59 (m, 2H), 7.48-7.42 (m, 1H), 7.29-7.24 (m,2H), 7.12 (s, 1H), 6.95-6.90 (m, 3H), 2.12 (s, 3H); LC-MS (ESI):Calculated mass: 455.16; Observed mass: 456.3 [M+H]⁺ (rt: 0.78 min).

Example 250N-(5-(5-(2-aminopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedure of Example 246 to afford the product in 97.6% yield (0.40 g).¹H NMR (400 MHz CD₃OD): 8.68 (s, 1H), 8.21-8.20 (d, 2H 7.91-7.88. (t,2H), 7.84-7.81 (dd, 1H), 7.70-7.68 (d, 1H), 7.66-7.64 (m, 1H), 7.54 (d,1H), 7.34-7.30 (m, 2H), 7.15-7.10 (m, 2H), 3.33 (s, 1H), 2.19 (s, 3H);Calculated mass: 455.46; Observed mass: 456.3 [M+H]⁺ (rt: 0.29 min).

Example 251N-(2′,4′-difluoro-5-(5-(thiazol-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) (200 mg,0.452 mmol) in THF (6 ml) using the method of Example 200(c) andthiazol-2-yl-zinc(II) bromide (310 mg, 1.35 mmol, 3.0 eq) to give theproduct in 25% yield (50 mg).

Example 252N-(5-(5-(6-aminopyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using themethod of Example 1(i). ¹H NMR (300 MHz, CD₃OD): δ 8.25 (d, 1H), 8.08(s, 2H), 7.96 (s, 1H), 7.82 (s, 1H), 7.59-7.51 (m, 3H), 7.42 (s, 1H),7.05-6.99 (m, 4H), 2.1 (s, 3H); LC-MS (ESI): Calculated mass: 455.16;Observed mass: 456.1 [M+H]⁺ (rt: 0.21 min).

Example 253N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea) tert-butyl(4-(1-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]-imidazol-5-yl)-1-methyl-1H-pyrazol-5-yl)carbamate

The compound was prepared from the compound of Example 1(h) using theprocedure mentioned in Example 1(i).

b)N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 253(a) (15 mg, 0.02 mmol) inDCM was added TFA (1 ml). The mixture was stirred at RT for 16 h andconcentrated to give the product in 50.4% yield (6 mg). ¹H NMR (400 MHz,CD₃OD): δ 8.49 (s, 1H), 8.11-8.10 (d, 1H), 7.86 (s, 1H), 7.73-7.60 (m,4H), 7.53-7.49 (m, 2H), 7.16-7.09 (m, 2H), 3.76 (s, 3H), 2.20 (s, 3H),1.97 (s, 2H). LC-MS (ESI): Calculated mass: 458.46; Observed mass: 459.0[M+H]⁺ (rt: 0.43 min).

Example 254N-(5-(5-(2-aminothiazol-5-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution ofN-(5-(5-(2-bromoacetyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(100 mg, 0.20 mmol) in ethanol was added thiourea (20 mg, 0.30 mmol, 1.5eq). The mixture was stirred at 60° C. for 3 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was distilled off to givethe crude residue which was purified by preparative HPLC to give theproduct in 14.7% yield (14 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.73 (s, 1H),8.11 (s, 1H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.62-7.50 (m, 2H), 7.45(d, 1H), 7.10-6.99 (m, 3H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass:461.4; Observed mass: 462.1 [M+H]⁺ (rt: 0.80 min).

Example 255N-(5-(5-(2-aminopyrimidin-5-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedure of Example 246. ¹H NMR (300 MHz, CD₃OD): δ 8.84 (s, 1H), 8.70(s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.86-7.83 (m, 1H), 7.72-7.61 (m,3H), 7.53 (d, 1H), 7.13-7.01 (m, 2H), 2.13 (s, 3H); LC-MS (ESI):Calculated mass: 456.4; Observed mass: 457.1 [M+H]⁺ (rt: 0.56 min).

Example 256N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methylpiperidine-4-carboxamide

The compound was prepared from the compound of Example 29(a) (50 mg,0.128 mmol) using the procedure of Example 225 using1-methylpiperidinecarboxylic acid (22 mg, 0.154 mmol, 1.2 eq.) to givethe product in 30% yield (20 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.59 (s,1H), 8.27 (d, 1H), 8.15-8.14 (t, 1H), 8.11 (m, 1H), 7.82-7.75 (m, 4H),7.66-7.56 (m, 1H), 7.56 (m, 1H), 7.13-7.11 (m, 1H), 6.56 (t, 1H),3.53-3.47 (m, 2H), 3.0 (m, 2H), 2.82 (s, 3H), 2.7 (m, 1H), 2.14-2.0 (m,4H). LC-MS (ESI): Calculated mass: 512.55; Observed mass: 513.1 [M+H]⁺(rt: 1.245 min).

Example 257 N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1, 1′-biphenyl]-3-yl)-2-(4-methylpiperazin-1-yl) acetamide

The compound was prepared from the compound of Example 29(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 10.12 (s, 1H),8.73 (s, 1H), 8.58 (d, 1H), 8.22 (d, 1H), 8.13 (t, 1H), 7.95-7.9 (m,2H), 7.82-7.71 (m, 3H), 7.55 (s, 1H), 7.47-7.41 (m, 1H), 7.28-7.23 (dt,1H), 6.55-6.54 (m, 1H), 3.45 (s, 2H), 3.17 (s, 3H), 2.48-2.32 (m, 8H);LC-MS (ESI): Calculated mass: 527.57; Observed mass: 528.2 [M+H]⁺ (rt:0.36 min).

Example 258N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide

The compound was prepared from the compound of Example 29(a) using theprocedure of Example 225. ¹H NMR (400 MHz, DMSO-d₆): δ 11.2 (s, 1H),8.75 (s, 1H), 8.57 (s, 1H), 8.22 (d, 1H), 8.07 (t, 1H), 8.0 (s, 1H),7.92-7.85 (m, 2H), 7.8-7.73 (m, 3H), 7.59 (s, 1H), 7.47-7.41 (dt, 1H),7.28-7.23 (dt, 1H), 6.54 (m, 1H), 5.24 (s, 2H): LC-MS (ESI): Calculatedmass: 496.47; Observed mass: 497.0 [M+H]⁺ (rt: 0.17 min).

Example 259N-(5-(5-(1H-pyrazol-1-yl)-11H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(piperidin-1-yl)acetamide

The compound was prepared from the compound of Example 29(a) using theprocedure of Example 225 and 2-(piperidin-1-yl) acetic acid (41 mg,0.290 mmol, 1.5 eq.) to give the product in 10.1% yield (10 mg). ¹H NMR(400 MHz, DMSO-d₆): δ 10.11 (s, 1H), 8.75 (s, 1H), 8.60 (d, 1H),8.24-8.21 (d, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.94-7.92 (dd, 1H),7.84-7.82 (d, 1H), 7.79-7.77 (m, 2H), 7.56 (s, 1H), 7.49-7.43 (t, 1H),6.57-6.56 (t, 1H), 3.14 (s, 2H); 2.67 (s, 1H); 2.33 (s, 1H); 1.90 (s,1H); 1.60-1.59 (t, 5H); 1.40 (s, 2H) LC-MS (ESI): Calculated mass:512.55; Observed mass: 513.2[M+H]⁺ (rt: 0.3 min).

Example 260N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(pyrrolidin-1-yl)acetamide

The compound was prepared from the compound of Example 29(a) using theprocedure of Example 225. ¹H NMR (600 MHz, CD₃OD): δ 8.62 (s, 1H),8.29-8.28 (d, 1H), 8.17-8.16 (t, 1H), 8.12 (s, 1H), 7.85-7.83 (dd, 3H),7.77-7.76 (d, 1H), 7.68-7.67 (m, 1H), 7.59 (s, 1H), 7.15-7.12 (m, 2H),6.58-6.57 (t, 1H), 3.73 (s, 2H); 3.02 (t, 4H); 2.00-1.94 (m, 7H); LC-MS(ESI): Calculated mass: 498.53, Observed mass: 499.6 [M+H]⁺ (rt: 0.6min).

Example 261N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-1-ethylpiperidine-3-carboxamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 225. ¹H NMR (300 MHz, DMSO): δ 10.6 (d, 1H), 9.50(s, 1H), 8.79 (d, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.00-7.96 (d, 2H),7.80-7.70 (m, 3H), 7.64-7.59 (m, 1H), 7.46 (m, 1H), 7.28 (m, 1H), 3.81(s, 3H), 3.60-3.56 (d, 3H), 3.43-3.37 (m, 1H), 3.14-3.04 (d, 2H),3.0-2.89 (t, 2H), 2.13 (d, 1H), 2.00-1.95 (d, 1H), 1.73-1.69 (d, 1H),1.55 (d, 1H); LC-MS (ESI): Calculated mass: 540.6; Observed mass: 541.2[M+H]⁺ (rt: 0.22 min).

Example 262N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-1-methylpiperidine-3-carboxamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 255. ¹H NMR (300 MHz, DMSO): δ 10.6 (d, 1H), 9.50(s, 1H), 8.79 (d, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.00-7.96 (d, 2H),7.80-7.70 (m, 3H), 7.64-7.59 (m, 1H), 7.46 (m, 1H), 7.28 (m, 1H), 3.81(s, 3H), 3.60-3.56 (d, 3H), 3.43-3.37 (m, 1H), 3.14-3.04 (d, 2H),3.0-2.89 (t, 2H), 2.13 (d, 1H), 2.00-1.95 (d, 1H), 1.73-1.69 (d, 1H),1.55 (d, 1H); LC-MS (ESI): Calculated mass: 526.58; Observed mass: 527.2[M+H]⁺ (rt: 0.15 min).

Example 263N-(2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixture the compound of Example 17(e) (250 mg, 0.644 mmol),4-azidotetrahydro-2H-pyran (90 mg, 0.77 mmol, 1.2 eq.), copper iodide(12 mg, 0.06 mmol, 0.1 eq.) in DMF was stirred at 90° C. for 16 h. Themixture was quenched with water and the precipitate formed was filteredand dried to give the crude product which was purified by preparativeHPLC to give the product in 45% yield (150 mg). ¹H NMR (300 MHz, DMSO):δ 10.4 (s, 1H) 8.77 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H),7.94-7.90 (m, 1H), 7.83-7.76 (m, 3H), 7.53 (s, 1H), 7.40-7.52 (m, 1H),7.34-7.22 (m, 1H), 4.80 (m, 1H), 4.02 (m, 2H), 3.50-3.52 (m, 2H), 2.10(s, 3H), 2.0-2.12 (m, 4H); LC-MS (ESI): Calculated mass: 514.5; Observedmass: 514.8 [M+H]⁺ (rt: 1.32 min).

Example 264N-(5-(5-(1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 17(e) (300 mg, 0.77 mmol), sodiumazide (150 mg, 2.32 mmol, 3.0 eq.), copper iodide (14 mg, 0.07 mmol, 0.1eq.) in DMF was stirred for 16 h at RT. The mixture was quenched withwater and the precipitate formed was filtered and dried to give thecrude product which was purified by preparative HPLC to give the productin 64.3% yield (200 mg). ¹H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 8.80 (s,1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.97-7.94 (d, 1H),7.85-7.76 (m, 3H), 7.56 (d, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 2.10 (s,3H); LC-MS (ESI): Calculated mass: 430.4; Observed mass: 431.2 [M+H]⁺(rt: 0.69 min). Example 265.

N-(5-(5-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Example 17(e) (100 mg, 0.25 mmol), sodiumazide (25 mg, 0.387 mmol, 1.5 eq.), (bromomethyl)cyclopropane (41 mg,0.310 mmol, 1.2 eq.), copper iodide (5 mg, 0.025 mmol, 0.1 eq.) in DMFwas stirred for 16 h at RT. The mixture was quenched with water and theprecipitate formed was filtered and dried to give the crude productwhich was purified by preparative HPLC to give the product in 80.6%yield (100 mg). ¹H NMR (300 MHz, CD₃OD): δ 10.4 (s, 1H) 8.68 (d, 1H),8.05 (s, 1H), 7.90-7.88 (m, 2H), 7.81-7.69 (m, 3H), 7.51-7.39 (m, 3H),7.28-7.22 (m, 1H), 4.25 (d, 2H), 2.10 (s, 3H), 1.34 (m, 1H), 0.63-0.56(2H, d), 0.50-0.46 (2H, d); LC-MS (ESI): Calculated mass: 484.5;Observed mass: 484.8 [M+H]⁺ (rt: 1.42 min).

Example 266N-(2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine(60 mg, 0.126 mmol) in DCM was added pyridine (19 mg, 2.52 mmol, 2.0eq.) followed by ethanesulfonyl chloride (19 mg, 0.152 mmol, 1.2 eq).After completion of the reaction the solvent was distilled off and thecrude product was purified by preparative HPLC to give the product in42% yield (30 mg). ¹H NMR (300 MHz, CD₃OD): δ 8.92 (s, 1H), 8.3 (d, 1H),8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77-7.69 (m,5H), 7.45 (m, 1H), 6.56 (m, 1H), 3.92 (s, 3H), 3.28-3.27 (m, 4H),1.6-1.49 (m, 6H); LC-MS (ESI): Calculated mass: 564.6; Observed mass:565.4 [M+H]⁺ (rt: 1.46 min).

Example 267N-(5-(5-(1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(70 mg, 0.18 mmol) in DCM was added pyridine (42 mg, 0.54 mmol, 3.0 eq.)followed by ethanesulfonyl chloride (27 mg, 0.216 mmol, 1.2 eq.). Thereaction was monitored by LCMS. After completion of the reaction thesolvent was distilled off and the crude product was purified bypreparative HPLC to give the product in 2.3% yield (2 mg).

Example 268N-(5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]-pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixtureN-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(300 mg, 0.77 mmol), sodium azide (76 mg, 1.15 mmol, 1.5 eq.),(bromomethyl)cyclopropane (125 mg, 0.92 mmol, 1.2 eq.), copper iodide(14 mg, 0.07 mmol, 0.1 eq.) in DMF was stirred for 16 h at RT. Themixture was quenched with water and the precipitate formed was filteredand dried to give the crude product which was purified by preparativeHPLC to give the product in 82.6% yield (310 mg). H NMR (300 MHz, DMSO):δ 10.4 (s, 1H) 8.99 (d, 2H), 8.80 (s, 1H), 8.63 (d, 1H), 8.30 (s, 1H),7.91 (d, 1H), 7.76-7.68 (m, 2H), 7.49-7.41 (m, 1H), 7.30-7.25 (m, 1H),4.21 (m, 2H), 2.12 (s, 3H), 1.23 (m, 1H), 0.63-0.60 (2H, d) 0.50-0.48(2H, d); LC-MS (ESI): Calculated mass: 485.4; Observed mass: 486.1[M+H]⁺ (rt: 1.52 min).

Example 269N-(2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A mixtureN-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(250 mg, 0.644 mmol), 4-azidotetrahydro-2H-pyran (90 mg, 0.77 mmol, 1.2eq.), copper iodide (12 mg, 0.06 mmol, 0.1 eq.) in DMF was stirred at90° C. for 16 h. The mixture was quenched with water and the precipitateformed was filtered and dried to give the crude product which waspurified by preparative HPLC to give the product in 45% yield (150 mg).¹H NMR (300 MHz, DMSO): δ 10.4 (s, 1H), 8.99-8.97 (m, 2H), 8.88 (s, 1H),8.61-8.60 (m, 1H), 8.32-8.29 (m, 1H), 7.91 (d, 1H), 7.76-7.68 (m, 2H),7.48-7.41 (m, 1H), 7.3-7.24 (m, 1H), 4.80 (m, 1H), 4.02 (m, 2H),3.50-3.60 (m, 2H), 2.10 (s, 3H), 2.0-2.12 (m, 4H); LC-MS (ESI):Calculated mass: 515.5; Observed mass: 516.5 [M+H]⁺ (rt: 1.37 min).

Example 270 Ethyl 2-(4-(3-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)acetate

A mixture ofN-(5-(5-ethynyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide(200 mg, 0.51 mmol), sodium azide (90 mg, 1.5 mmol, 3.0 eq.), ethyl2-bromoacetate (100 mg, 0.61 mmol, 1.2 eq.), sodium ascorbate (100 mg,0.51 mmol, 1.0 eq.) and copper sulfate pentahydrate (45.9 mg, 0.255mmol, 0.5 eq.) in DMSO, THF and water (1:1:1, 3 ml) was stirred for 12 hat RT. The mixture was quenched with water and the precipitate formedwas filtered and dried to give the crude product which was purified bypreparative HPLC to give the product in 76% yield (200 mg). ¹H NMR (300MHz, DMSO): δ 10.4 (s, 1H) 9.02-8.99 (d, 2H), 8.75 (s, 1H), 8.64 (d,1H), 8.29 (s, 1H), 7.92 (d, 1H), 7.71-7.70 (m, 2H), 7.50-7.40 (m, 1H),7.27 (m, 1H), 5.55 (s, 2H), 4.22 (q, 2H), 2.10 (s, 3H), 1.24 (t, 3H);LC-MS (ESI): Calculated mass: 517.45; Observed mass: 517.8 [M+H]⁺ (rt:1.47 min).

Example 271 2-(4-(3-(5-acetamido-2′, 4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4, 5-b]pyridin-6-yl)-1H-1, 2,3-triazol-1-yl) acetamide

To a mixture of the compound of Example 270 (100 mg, 0.19 mmol) inmethanol was added methonalic ammonia at 0° C. and the mixture wasstirred at RT for 16 h. The mixture was distilled completely and thecrude product was purified by preparative HPLC to give the product in13% yield (12 mg). δ 10.5 (s, 1H) 9.14-8.97 (d, 2H), 8.82 (s, 1H), 8.76(d, 1H), 8.35 (s, 1H), 7.89 (d, 1H), 7.81-7.80 (m, 2H), 7.65-7.55 (m,1H), 7.27 (m, 1H), 5.55 (s, 2H), 2.8 (s, 2H), 2.10 (s, 3H); LC-MS (ESI):Calculated mass: 515.5; Observed mass: 516.5 [M+H]⁺ (rt: 1.37 min).

Example 272N-(5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixtureN-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(300 mg, 0.77 mmol), sodium azide (75 mg, 1.15 mmol, 1.5 eq.), copperiodide (14 mg, 0.07 mmol, 0.1 eq.) in DMF was stirred for 16 h at RT.The mixture was quenched with water and the precipitate formed wasfiltered and dried to give the crude product which was purified bypreparative HPLC to give the product in 90% yield (300 mg).

Example 273N-(5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(70 mg, 0.179 mmol) in DCM was added pyridine (42 mg, 0.53 mmol, 3.0eq.) followed by ethanesulfonyl chloride (20 mg, 0.179 mmol, 1.0 eq.).The reaction was monitored by LCMS. After completion of the reaction thesolvent was distilled off and the crude product was purified bypreparative HPLC to give the product in 9.3% yield (8 mg). ¹H NMR (300MHz, DMSO): δ 10.4 (s, 1H) 9.0-8.97 (m, 2H), 8.64 (d, 1H), 7.92 (s, 1H),7.75-7.64 (m, 3H), 7.47-7.43 (m, 3H), 3.31-3.24 (q, 2H), 1.39-1.34 (t,3H); LC-MS (ESI): Calculated mass: 481.4; Observed mass: 481.8 [M+H]⁺(rt: 1.36 min).

Example 274N-(2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine(65 mg, 0.136 mmol) in DCM was added pyridine (21 mg, 2.72 mmol, 2.0eq.) followed by ethanesulfonyl chloride (21 mg, 0.164 mmol, 1.2 eq.).After completion of the reaction the solvent was distilled off and thecrude product was purified by preparative HPLC to give the product in42% yield (30 mg). ¹H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.04 (s, 1H),8.99-8.98 (d, 1H), 8.90 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H),7.76-7.70 (m, 2H), 7.49 (m, 2H), 7.35 (d, 1H), 4.82 (m, 1H), 3.95 (d,2H), 3.58-3.55 (t, 2H), 3.36-3.28 (m, 2H), 2.12 (m, 2H), 1.29-1.24 (t,3H), 1.08-1.06 (t, 2H); LC-MS (ESI): Calculated mass: 565.5; Observedmass: 565.9 [M+H]⁺ (rt: 1.44 min).

Example 275N-(5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]-pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(50 mg, 0.112 mmol) in DCM was added pyridine (26 mg, 0.33 mmol, 3.0eq.) and ethanesulfonyl chloride (17 mg, 0.135 mmol, 1.2 eq.). Aftercompletion of the reaction the solvent was distilled off and the crudeproduct was purified by preparative HPLC to give the product in 33%yield (20 mg). ¹H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 9.02-8.99 (m, 2H),8.81 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.77-7.69 (m, 2H),7.49-7.42 (m, 2H), 7.31-7.25 (d, 1H), 4.33 (d, 2H), 3.42-3.26 (m, 2H),1.34-1.24 (t, 3H), 0.63-0.60 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI):Calculated mass: 535.5; Observed mass: 535.8 [M+H]⁺ (rt: 0.1.33 min).

Example 276N-(5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanecarboxamide

To a solution of5-(6-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(50 mg, 0.11 mmol) in DMF was added cyclopropanecarboxylic acid (11 mg,0.13, mmol, 1.2 eq.) followed by HATU (91 mg, 0.24 mmol, 2.0 eq.) andDIPEA (43 mg, 0.33 mmol, 3.0 eq). The mixture was stirred for 16 h andquenched extracted as in Example 1(d). The solvent was distilled off toafford the crude residue which was purified by column chromatography togive the product in 51% yield (25 mg). ¹H NMR (300 MHz, DMSO): δ 10.6(s, 1H) 8.99 (d, 2H), 8.88 (d, 1H), 8.62 (d, 1H), 8.31 (d, 1H), 7.92 (d,1H), 7.76-7.71 (m, 2H), 7.47-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.33-4.30(d, 2H), 3.64-3.62 (m, 2H), 3.12-3.09 (m, 2H), 1.87-1.83 (m, 1H),0.63-0.61 (t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass:511.5; Observed mass: 511.8 [M+H]⁺ (rt: 1.63 min).

Example 277N-(3-(3-fluoropyridin-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl) acetamide a)N-(3-bromo-5-((4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl) amino)phenyl) acetamide

A solution of 4-(4-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole (1.6 g,7.239 mmol), N-(3-amino-5-bromophenyl)acetamide (1.98 g, 8.687 mmol) andpotassium fluoride (0.503 g, 8.687 mmol) in DMF was heated at 130° C.for 48 h. The mixture was quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude residue which was purifiedby column chromatography (60-120 silica gel, 50% ethyl acetate inhexane) to yield the title product in 35% yield (1.1 g); LC-MS (API):Calculated mass: 430.1; Observed mass: 432 [M+H]⁺ (rt: 1.50 min).

b)N-(3-((2-amino-4-(1-methyl-1H-pyrazol-4yl)-phenyl)amino)-5-bromophenyl)acetamide

To a solution of the compound of Example 277(a) (1.0 g, 2.32 mmol) inTHF (20 ml) and methanol (20 ml) were added a solution of ammoniumchloride (1.24 g, 23.20 mmol, 10 eq.) in water (15 ml) and zinc (1.5 g,23.20 mmol, 10 eq.). The mixture was stirred at RT for 4 h and filtered.The filtrate was diluted with water and extracted as in Example 1(d).The solvent was distilled off to give the title product in 90% yield(0.9 g); LC-MS (API): Calculated mass: 399.1; Observed mass: 400.0[M+H]⁺ (rt: 0.61 min).

c)N-(3-bromo-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-phenyl)acetamide

A mixture of the compound of Example 277(b) (1.0 g, 2.50 mmol) andformic acid (10 ml) was heated at 90° C. for 2 h. The formic acid wasdistilled off and the residue was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to give the product in 85% yield(0.9 g); LC-MS (ESI): Calculated mass: 410.1; Observed mass: 412.1[M+H]⁺ (rt: 0.403 min).

d)N-(3-(3-fluoropyridin-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl) acetamide

A solution of the compound of Example 277(c) (0.1 g, 0.243 mmol) in1,2-dimethoxyethane (4 ml) was degassed by N₂ bubbling for 5 min.(3-Fluoropyridin-4-yl)-boronic acid (0.041 g, 0.292 mmol, 1.2 eq.) wasadded and the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.020g, 0.024 mmol, 0.1 eq.) and aqueous sodium carbonate (0.077 g, 0.731mmol, 3.0 eq.) were added and the procedure of Example 1(d) wasfollowed. The crude residue of the product was purified by preparativeHPLC to give the product in 21% yield. ¹HNMR (300 MHz, DMSO-d₆): δ 10.5(s, 1H), 8.97 (s, 1H), 8.75 (s, 1H), 8.59 (d, 1H), 8.24 (s, 1H), 8.20(s, 1H), 8.01 (s, 1H), 7.97 (d, 2H), 7.80-7.65 (m, 4H), 3.89 (s, 3H),2.13 (s, 3H); LC-MS (ESI): Calculated mass: 426.16; Observed mass: 427.1[M+H]⁺ (rt: 0.20 min).

Example 278N-(3-(3-fluoropyridin-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)ethanesulfonamide

The compound was prepared from the compound of Example 277 (0.9 g, 2.11mmol, 1 eq.) using the procedure of Example 2 and ethanesulfonylchloride (60 mg, 0.46 mmol, 1.2 eq.) to give the product in 15.13% yield(28 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.69-8.68 (d, 1H), 8.58 (s, 1H),8.54-8.52 (d, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.74-7.71(t, 1H), 7.67-7.64 (d, 1H), 7.58-7.56 (d, 1H), 7.44-7.43 (t, 1H),7.36-7.33 (d, 2H), 3.87 (s, 3H), 3.07-3.02 (quartet, 2H), 1.22-1.18 (t,3H); LC-MS (ESI): Calculated mass: 476.14; Observed mass: 476.9 [M+H]⁺(rt: 0.36 min).

Example 279N-(3-(3-chloropyridin-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamide

The compound was prepared from the compound of Example 277(c) using theprocedure of Example 277(d). ¹HNMR (400 MHz, DMSO-d₆): δ 10.5 (s, 1H),8.80 (m, 2H), 8.66-8.63 (m, 2H), 8.20 (s, 1H), 8.13 (s, 1H), 7.99 (s,1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.60 (d,1H), 7.53 (s, 1H), 3.88 (s, 3H), 2.13 (s, 3H); LC-MS (ESI): Calculatedmass: 442.13; Observed mass: 443.1 [M+H]⁺ (rt: 0.28 min).

Example 280 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)pyrimidin-2-amine

A solution of1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole(0.075 g, 0.161 mmol) in 1,4-dioxane (3 ml) was degassed by N₂ bubblingfor 5 min. Pyrimidin-2-amine (0.018 g, 0.193 mmol, 1.2 eq.) was addedand the mixture was degassed for another 5 min. Pd₂(dba)₃ (0.014 g,0.016 mmol, 0.1 eq.) and xantphos (0.037 g, 0.064 mmol, 0.4 eq.) andCs₂CO₃ (0.209 g, 0.644 mmol, 4.0 eq) were added sequentially and themixture was further degassed for 5 min. and then heated at 110° C. for16 h. The mixture was filtered on celite bed, quenched and extracted asin Example 1(d). The solvent was distilled off to afford the cruderesidue which was purified by column chromatography (60-120 silica gel,2% methanol in ethyl acetate) to yield the title product in 11.6% yield(0.09 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H), 8.83 (S, 1H),8.57-8.56 (D, 2H), 8.35 (s, 1H), 8.24 (s, 1H), 8.01-7.97 (s, 3H),7.84-7.81 (d, 1H), 7.70-7.68 (m, 2H), 7.46-7.432 (m, 2H), 7.280-7.286(m, 1H), 6.95-6.32 (t, 1H), 3.88 (s, 1H), LC-MS (ESI): Calculated mass:479.48; Observed mass: 480.1 [M+H]⁺ (rt: 1.52 min).

Example 281 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl) thiazol-2-amine

The compound was prepared from1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole(0.05 g, 0.107 mmol) using the procedure of Example 280 andthiazol-2-amine (0.01 g, 0.10 mmol, 1.0 eq.) to yield the title productin 11.7% yield (0.06 g). ¹H NMR (400 MHz CD₃OD): δ 9.45 (s, 1H), 8.39(s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.86-7.83 (m, 2H),7.74 (s, 1H), 7.67-7.65 (m, 1H), 7.45 (s, 1H), 7.28-7.27 (d, 1H),7.16-7.11 (m, 2H), 6.89 (d, 1H), 3.95 (s, 3H) LC-MS (ESI): Calculatedmass: 484.52; Observed mass: 485.2 [M+H]⁺ (rt: 1.01 min).

Example 282 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-1-methyl-1H-pyrazol-3-amine

The compound was prepared from1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazoleusing the procedure of Example 280. ¹H NMR (400 MHz CD₃OD): δ 8.72 (s,1H), 8.19 (s, 1H), 7.97-7.90 (m, 3H), 7.79-7.77 (d, 1H), 7.70 (m, 1H),7.63-7.61 (d, 1H), 7.56-7.55 (d, 1H), 7.45-7.40 (m, 2H), 7.23 (m, 1H),7.13 (s, 1H), 5.86-5.85 (d, 1H), 3.87 (s, 3H), 3.74 (s, 3H) LC-MS (ESI):Calculated mass: 481.50; Observed mass: 482.1 [M+H]⁺ (rt: 1.45 min).

Example 283N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-1-methyl-1H-pyrazol-4-amine

The compound was prepared from1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazoleusing the procedure of Example 280. ¹H NMR (400 MHz, DMSO-d₆): δ 9.13(s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.02-8.00. (d, 2H), 7.821 (s, 1H),7.74-7.70 (m, 3H), 7.48 (m, 2H), 7.29 (m, 1H), 7.09-7.04 (m, 3H), 3.92(s, 3H), 3.84 (s, 3H), Calculated mass: 481.50 observed mass: 482.1[M+H]⁺ (rt: 1.36 min).

Example 284N-(2′,4′-difluoro-5-(5-(1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from4-(4-(1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol(88 mg, 0.185 mmol) using the procedure of Example 2(b) andethanesulfonyl chloride (28.6 mg, 0.370 mmol, 1.2 eq.) to give theproduct in 33.6% yield (35 mg)¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s,1H), 8.92 (s, 1H), 8.30 (s, 1H), 8.01.-7.97 (d, 2H), 7.69 (m, 3H), 7.59(d, 2H), 7.56 (m, 2H), 7.32 (m, 1H), 4.30 (m, 2H), 3.31-3.28 (m, 4H),1.8 (m, 2H), 1.28-1.24 (t, 3H), 1.15 (s, 6H), Calculated mass: 565.63;Observed mass: 566.2 [M+H]⁺ (rt: 1.40 min).

Example 285N-(2′,4′-difluoro-5-(6-(6-oxo-1,6-dihydropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution ofN-(5-(6-(6-(benzyloxy)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(0.10 g, 0.182 mmol) in TFA (4 ml) was stirred at RT for 16 h. Themixture was concentrated on vacuo, quenched with sodium bicarbonate andextracted as in Example 1(d). The solvent was distilled off to give theproduct in 84.3% yield (0.70 g)¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s,1H), 8.98 (s, 1H), 8.68-8.67 (D, 1H), 8.43 (d, 1H), 8.31 (s, 1H),7.99-7.96 (dd, 1H), 7.89 (s, 2H), 7.76-7.70 (m, 2H), 7.49-7.43 (m, 1H),7.31-7.26 (m, 1H), 6.51-6.48 (d, 1H), 2.13 (s, 3H); LC-MS (ESI):Calculated mass 457.43: Observed mass: 458.1[M+H]⁺ (rt: 0.68 min).

Example 286N-(2′,4′-difluoro-5-(6-(6-oxo-1,6-dihydropyridin-3-yl)-3H-imidazo[4,5-b]-pyridin-3-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

A solution ofN-(5-(6-(6-(benzyloxy)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide(0.140 g, 0.234 mmol) in TFA (5 ml) was stirred at RT for 16 h. Themixture was concentrated on vacuo, quenched with sodium bicarbonate andextracted as in Example 1(d). The solvent was distilled off to give theproduct in 23.7% yield (0.028 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s,1H), 9.07 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.01 (d, 1H), 7.93 (s,2H), 7.78-7.72 (m, 2H), 7.48-7.45 (d, 2H), 7.30-7.26 (t, 1H), 6.52-6.50(d, 1H), 3.30-3.28 (q, 2H), 1.28-1.25 (t, 3H); LC-MS (ESI): Calculatedmass: 507.51; Observed mass: 508.1 [M+H]⁺ (rt: 0.1 min).

Example 287N-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared fromN-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(0.15 g, 0.274 mmol) using the procedure of Example 286 to afford theproduct in 11.2% yield (0.014 g). ¹H NMR (400 MHz, CD₃OD): δ 8.92 (s,1H), 8.20-8.19 (s, 1H), 8.05-8.02 (dd, 1H), 7.94 (s, 1H), 7.83-7.78 (m,2H), 7.74 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (s, 1H), 7.16-7.09 (m, 2H),6.69-6.67 (d, 1H), 2.65 (s, 5H), 2.19 (s, 3H); LC-MS (ESI): Calculatedmass 456.44: Observed mass: 457.1[M+H]⁺ (rt: 0.68 min).

Example 288N-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethane sulfonamide

The compound was prepared fromN-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide(0.25 g, 0.419 mmol) using the procedure of Example 286 to afford theproduct in 82.5% yield (0.175 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s,1H), 9.06 (S, 1H), 8.025-7.954 (m, 2H), 7.83-7.84 (d, 1H), 7.82-7.72 (m,2H), 7.68-7.66 (d, 1H), 7.61 (s, 2H), 7.50-7.43 (m, 2H), 7.31-7.26 (t,1H), 6.50-6.47 (d, 1H), 3.33-3.27 (q, 2H), 1.28-1.24 (t, 3H), LC-MS(ESI): Calculated mass: 506.52; Observed mass: 507.0 [M+H]⁺ (rt: 0.085min).

Example 289N-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(0.145 g, 0.238 mmol) using the procedure of Example 286 to afford theproduct in 6.1% yield (0.09 g). ¹H NMR (400 MHz, CD₃OD): δ 9.19 (s, 1H),8.07-8.04 (dd, 1H), 7.99 (s, 1H), 7.85-7.82 (dd, 2H), 7.76-7.71 (m, 2H),7.90 (m, 2H), 7.64-7.59 (m, 1H), 7.15-7.13 (m, 2H), 6.71-7.68 (d, 1H),2.76-2.72 (m, 1H), 1.17-1.12 (m, 2H), 1.06-1.02 (m, 2H), Calculatedmass: 518.53; Observed mass: 519.3 [M+H]⁺ (rt: 0.8 min).

Example 290 N-(5-(6-(2-aminopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution of tert-butyl(5-(3-(5-(cyclopropanesulfonamido)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)carbamate(0.2 g, 0.32 mmol) in DCM (5 ml) was added TFA (1.2 ml) at 0° C. Themixture was stirred at RT for 16 h. The mixture was concentrated onvacuo, quenched with sodiumbicarbonate and extracted as in Example 1(d).The solvent was distilled off to afford the product in 17.9% yield (0.30g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H), 9.09 (S, 1H), 8.90 (s,1H), 8.69 (s, 1H), 8.04-8.03 (d, 1H), 7.93 (s, 1H), 7.79 (s, 1H),7.74-7.72 (d, 1H), 7.50 (s, 1H), 7.45-7.38 (m, 2H), 7.34 (s, 1H),7.30-7.26 (t, 1H), 2.76-2.72 (m, 1H), 1.17-1.12 (m, 2H), 1.06-1.02 (m,2H); LC-MS (ESI): Calculated mass: 518.54; Observed mass: 519.2 [M+H]⁺(rt: 0.71 min).

Example 291N-(5-(5-(2-aminopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from tert-butyl(5-(1-(5-(cyclopropanesulfonamido)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)-carbamate(0.2 g, 0.32 mmol) using the procedure of Example 290 to afford theproduct in 9.0% yield (0.18 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.32 (s,1H), 8.84 (s, 1H), 8.30 (s, 1H), 8.05-8.03. (s, 3H), 7.88-7.86 (d, 1H),7.82-7.79 (m, 2H), 7.62-7.60 (d, 2H), 7.52-7.47 (m, 2H), 7.39-7.38 (d,1H), 7.31-7.29 (m, 2H), 1.03-1.01 (d, 4H), Calculated mass: 517.55;Observed mass: 518.1 [M+H]⁺ (rt: 0.41 min).

Example 292N-(2′,4′-difluoro-5-(5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

A solution ofN-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(0.15 g, 0.272 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N₂bubbling for 5 min. 2-Bromo-5-methyl-1,3,4-thiadiazole (0.058 g, 0.326mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min.Pd(dppf)Cl₂ (0.011, 0.013 mmol, 0.05 eq.) and aqueous sodium carbonate(0.072, 0.680 mmol, 2.5 eq.) were added and the procedure of Example1(d) was followed. The crude residue of the product was purified bycolumn chromatography (60-120 silica gel, 80% ethyl acetate in hexane)to yield the desired title product in 4.2% yield (0.006 g). ¹H NMR (400MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.81 (s, 1H), 8.34-8.33 (s, 1H),8.00-7.98 (dd, 1H), 7.84 (d, 1H), 7.79-7.73 (m, 1H), 7.54 (s, 1H),7.49-7.42 (m, 2H), 7.29-7.24 (m, 1H), 3.17-3.16 (d, 2H), 2.85-2.84 (m,1H), 2.79 (s, 3H), 1.01-0.99 (m, 4H); LC-MS (ESI): Calculated mass:523.58; Observed mass: 523.7 [M+H]⁺ (rt: 1.50 min).

Example 293 N-(2′,4′-difluoro-5-(5-(5-fluoropyridin-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

A solution ofN-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(0.15 g, 0.272 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N₂bubbling for 5 min. 2-Bromo-5-fluoropyridine (0.057 g, 0.326 mmol, 1.2eq.) was added and the mixture was degassed for another 5 min.Pd(dppf)Cl₂ (0.011, 0.013 mmol, 0.05 eq.) and aqueous sodium carbonate(0.072, 0.680 mmol, 2.5 eq.) were added and the procedure of Example1(d) was followed. The crude residue of the product was purified bycolumn chromatography (60-120 silica gel, 80% ethyl acetate in hexane)to yield the title product in 14.1% yield (0.02 g). ¹H NMR (400 MHz,DMSO-d₆): δ 10.23 (s, 1H), 8.75 (s, 1H), 8.68-8.67 (d, 1H), 8.48 (d,1H), 8.20-8.13 (m, 2H), 7.86-7.743 (m, 3H), 7.61-7.60 (d, 2H), 7.51-7.43(m, 2H), 7.30-7.25 (m, 1H), 2.89-2.86 (t, 1H), 1.03-1.02 (d, 4H); LC-MS(ESI): Calculated mass: 520.53; Observed mass: 521.2 [M+H]⁺ (rt: 1.64min).

Example 294N-(3-(3-fluoropyridin-2-yl)-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)methanesulphonamide a)N-(3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

To a degassed (N₂ bubbling) solution ofN-(3-bromo-5-nitrophenyl)acetamide (25 g, 96.89 mmol) in 1,4-dioxane(150 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (29.5 g,116.27 mmol, 1.2 eq), Pd(dppf)Cl₂ (7.9 g, 9.68 mmol, 0.1 eq.) andpotassium acetate (28.5 g, 290.69 mmol, 3 eq.). The mixture was heatedat 100° C. in a sealed tube for 6 h. The mixture was diluted with ethylacetate and filtered over a pad of celite. The solvent was distilled offto afford the product (24 g) ¹HNMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H),8.72 (t, 1H), 8.18-8.15 (m, 1H), 8.03 (d, 1H), 2.08 (s, 1H), 1.30 (s,9H).

b) N-(3-(3-fluoropyridin-2-yl)-5-nitrophenyl)acetamide

A solution ofN-(3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-acetamide(10 g, 32.67 mmol) in 1,2-dimethoxyethane (100 ml) was degassed by N₂bubbling for 5 min. 2-Chloro-3-fluoro pyridine (4.29 g, 32.67 mmol) wasadded and the mixture was degassed for another 5 min. Pd(dppf)cl₂ (2.6g, 3.26 mmol) and aqueous sodium carbonate (10.39 g, 98.03 mmol) wereadded and the procedure of Example 1(d) was followed. The crude residueof the product was purified by column chromatography (60-120 silica gel,3% methanol in chloroform) to yield the title product in 70% yield (6.3g). ¹H NMR (300 MHz, DMSO-d₆): δ10.64 (s, 1H), 8.74 (m, 1H), 8.62 (m,1H), 8.55 (brs, 1H), 8.44 (brs, 1H), 7.93 (m, 1H), 7.60 (m, 1H), 2.12(s, 3H).

c) N-(3-amino-5-(3-fluoropyridin-2-yl)phenyl)acetamide

To a solution of N-(3-(3-fluoropyridin-2-yl)-5-nitrophenyl)acetamide (5g, 18.18 mmol) in THF (50 ml), Zn (11.8 g, 181.18 mmol) was addedfollowed by slow addition of solution of NH₄Cl (9.7 g, 181.18 mmol) in20 ml water. The mixture was stirred at RT for 1 h. The mixture wasfiltered through celite and bed washed with ethyl acetate. The mixturewas diluted with ethyl acetate and washed with water and brine solution,dried over sodium sulphate and distilled to give the product in 90%yield (4.2 g). LC-MS (ESI): Calculated mass: 245; Observed mass: 246.1[M+H]⁺ (rt: 0.21 min).

d)N-(3-((4-bromo-2-nitrophenyl)amino)-5-(3-fluoropyridin-2-yl)phenyl)acetamide

Solution of 4-bromo-1-fluoro-2-nitrobenzene (3.0 g, 13.63 mmol),N-(3-amino-5-(3-fluoropyridin-2-yl)phenyl)acetamide (4.0 g, 16.36 mmol),and potassium fluoride (0.95 g, 16.36 mmol) in DMF was heated at 130° C.for 16 h. The mixture was quenched and extracted as in Example 1(d). Thesolvent was distilled off to afford the crude residue which was purifiedby column chromatography (60-120 silica gel, 30% ethyl acetate inhexane) to yield the title product in 50% yield (3.4 g). ¹H NMR (300MHz, DMSO-d₆): δ 8.55 (brs, 1H), 8.23 (brs, 1H), 7.96 (m, 2H), 7.85 (m,2H), 7.67 (d, 1H), 7.51 (m, 2H), 7.21 (d, 1H), 2.07 (s, 3H).

e)N-(3-((2-amino-4-bromophenyl)amino)-5-(3-fluoropyridin-2-yl)phenyl)acetamide

To a solution of the compound of Example 294(d) (3.4 g, 7.64 mmol) inTHF (35 ml) were added a solution of ammonium chloride (4.08 g, 76.40mmol, 10 eq.) in water (15 ml) and zinc (4.98 g, 76.40 mmol, 10 eq.).The mixture was stirred at RT for 4 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the title product in 75% yield (2.4 g). LC-MS(API): Calculated mass: 415.2, Observed mass: 417.1 [M+H]⁺ (rt: 1.35min).

f)N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(3-fluoropyridin-2-yl)phenyl)-acetamide

A mixture of the compound of Example 294(e) (2.4 g, 5.78 mmol) andformic acid (24 ml) was heated at 90° C. for 6 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the title product in73% yield (1.8 g). LC-MS (ESI): Calculated mass: 425.2; Observed mass:426.7 [M+H]⁺ (rt: 1.38 min).

g) 3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(3-fluoropyridin-2-yl)aniline

To a solution of the compound of Example 294(f) (0.6 g, 1.41 mmol) inethanol (20 ml) was added solution of NaOH (0.56 g, 14.11 mmol) in 5 mlof water and the mixture was heated at 90° C. for 2 h. The mixture wasconcentrated and the crude residue was quenched with water and extractedas in Example 1(d). The solvent was distilled off to afford the productin 55% yield (0.3 g). LC-MS (API): Calculated mass: 382.0; Observedmass: 385.1 [M+H]⁺ (rt: 1.32 min).

h) N-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(3-fluoropyridin-2-yl)phenyl methane sulphonamide

To a solution of the compound of Example 294(g) (0.15 g, 0.39 mmol) inDCM was added pyridine (0.093 g, 1.17 mmol) followed by methane sulfonylchloride (0.054 g, 0.47 mmol). The mixture was stirred for 3 h, quenchedwith water and extracted as in Example 2(b). The solvent was distilledoff to afford the crude residue which was purified by 60-120 meshsilicagel, to give the product in 60% yield (120 mg). LC-MS (ESI):Calculated mass: 460.1; Observed mass: 460.2 [M+H]⁺ (rt: 1.54 min).

i)N-(3-(3-fluoropyridin-2-yl)-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)methanesulfonamide

A solution of the compound of Example 294(h) (0.12 g, 0.260 mmol) in1,2-dimethoxyethane (8 ml) was degassed by N₂ bubbling for 5 min.4-(2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (0.096 g, 0.313 mmol) was added and the mixture was degassedfor another 5 min. Aqueous sodium carbonate (0.083 g, 0.782 mmol) andPd(dppf)Cl₂ (0.021 g, 0.026 mmol) were added and the procedure ofExample 1(d) was followed. The crude residue of the product was purifiedby preparative HPLC to give the title product in 10% yield (15 mg). ¹HNMR (400 MHz, CD₃OD): δ 8.56 (d, 2H), 8.11 (s, 1H), 7.94-7.90 (m, 4H),7.80-7.72 (m, 2H), 7.66-7.62 (m, 2H), 7.52-7.50 (m, 1H), 4.33 (t, 2H),3.68-3.64 (m, 4H), 3.12 (s, 3H), 2.85 (m, 2H), 2.52 (m, 4H); LC-MS(ESI): Calculated mass: 561.2; Observed mass: 561.8 [M+H]⁺ (rt: 0.10min).

Example 295N-(3-(3-fluoropyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)cyclopropanesulfonamide

The compound was prepared fromN-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(3-fluoropyridin-2-yl)phenyl)cyclopropanesulfonamide(150 mg, 0.30 mmol) using the method of Example 1(i) to give the productin 15% yield (10 mg). ¹H NMR (400 MHz, CDCl3): δ 8.53 (d, 1H), 7.92 (d,3H), 7.80 (s, 1H), 7.72 (d, 2H), 7.6.3-7.55 (m, 4H), 7.41-7.28 (m, 1H),3.92 (s, 3H), 2.85-2.80 (m, 1H), 1.31-1.17 (m, 2H) 1.03-1.01 (m, 2H);LC-MS (ESI): Calculated mass: 488.5; Observed mass: 489.0 [M+H]⁺ (rt:0.59 min).

Example 296N-(3-(3-methoxypyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)cyclopropanesulfonamide

The compound was prepared fromN-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)-5-(3-methoxypyridin-2-yl)phenyl)cyclopropanesulfonamide(200 mg, 0.40 mmol) using the procedure of Example 1(i) to give thetitle product in 20% yield (20 mg). ¹H NMR (400 MHz, DMSO): δ 10.3 (s,1H), 8.60 (d, 1H), 8.32-8.31 (d, 1H), 8.20 (s, 1H) 7.99 (d, 1H), 7.94(s, 1H), 7.92-7.89 (d, 2H), 7.66-7.63 (m, 3H), 7.54 (d, 1H), 7.47-7.43(m, 1H), 4.33 (d, 2H), 3.42-3.26 (m, 2H), 1.34-1.24 (t, 3H), 0.63-0.60(t, 2H), 0.49-0.48 (t, 2H); LC-MS (ESI): Calculated mass: 500.5;Observed mass: 500.8 [M+H]⁺ (rt: 0.45 min).

Example 297N-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamidea)N-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

To a degassed (N₂ bubbling) solution of of compound of Example 1(h) (0.3g, 0.68 mmol) in 1,2-dimethoxyethane (10 ml) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.26 g,1.02 mmol, 1.5 eq.), Pd(dppf)Cl₂ (55 mg, 0.068 mmol, 0.1 eq.) andpotassium acetate (0.2 g, 2.04 mmol, 3 eq.) and the mixture was heatedat 80° C. in a sealed tube for 3 h. The mixture was diluted with ethylacetate and filtered over a pad of celite. The solvent was distilled offto afford the crude residue which was purified by column chromatography(60-120 silica gel, 70% ethyl acetate in hexane) to yield the titleproduct in 60% yield (0.2 g). LC-MS (ESI): Calculated mass: 489.32;Observed mass: 490.5 [(M+H]⁺ (rt: 1.83 min).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 297(a) (0.1 g, 0.204 mmol) in1,2-dimethoxyethane (15 ml) was degassed by N₂ bubbling for 5 min.4-Bromo-1-methyl imidazole (49 mg, 0.306 mmol, 1.5 eq.) was added andthe mixture was degassed for another 5 min. Pd(dppf)Cl₂ (16 mg, 0.0204mmol, 0.1 eq.) and aqueous sodium carbonate (65 mg, 0.612 mmol, 3.0 eq.)were added and the procedure of Example 1(d) was followed. The cruderesidue of the product was purified by column chromatography (60-120silica gel, 5% methanol in chloroform) to yield the title product in 11%yield (10 mg). ¹H NMR (400 MHz, DMSO-d6): δ 10.5 (s, 1H), 9.05-9.0 (brS, 1H), 8.8 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.87-7.76(m, 5H), 7.56 (s, 1H), 7.48 (dt, 1H), 7.3-7.29 (dt, 1H), 3.9 (s, 3H),2.15 (s, 3H); LC-MS (ESI): Calculated mass: 443.45; Observed mass: 444.1[M+H]⁺ (rt: 0.632 min).

Example 2981-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)ureaa)2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine

The compound was prepared from the compound of Example 297 (0.4 g, 2.26mmol) using the procedure of Example 2(a) to afford the product in 27%yield (0.1 g). LC-MS (ESI): Calculated mass: 401.41; Observed mass:402.1 [M+H]⁺ (rt: 1.198 min).

b)1-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 298(a) (50 mg, 0.124 mmol) inDCM was added furfuryl isocyanate (0.01 ml, 0.149 mmol, 1.2 eq.)followed by DIPEA (0.06 ml, 0.37 mmol, 3 eq.). The mixture was stirredfor overnight and quenched and extracted as in Example 1(d). The solventwas distilled off to afford the crude residue which was purified bypreparative HPLC to give the product in 40% yield (20 mg). ¹H NMR (300MHz, DMSO-d6): δ 9.16 (s, 1H), 9.14 (s, 1H), 8.8 (s, 1H), 8.27-8.22 (d,2H), 7.99 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.81-7.73 (m, 2H), 7.62(s, 2H), 7.49-7.42 (m, 2H), 7.31-7.26 (dt, 1H), 6.91-6.88 (t, 1H),6.44-6.42 (m, 1H), 6.3-6.29 (m, 1H), 4.35-4.33 (d, 2H), 3.94 (s, 3H).LC-MS (ESI): Calculated mass: 524.52; Observed mass: 525 [M+H]⁺ (rt:0.632 min).

Example 299N-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 298(a) using theprocedures of Example 294(h). ¹H NMR (300 MHz, CD₃OD): δ 8.4 (s, 1H),8.0 (s, 1H), 7.71-7.69 (dd, 1H), 7.59-7.41 (m, 6H), 7.04-7.01 (m, 2H),3.69 (S, 3H), 3.22-3.13 (q, 2H), 1.29-1.26 (t, 3H); LC-MS (ESI):Calculated mass: 493.53; Observed mass: 494 [M+H]⁺ (rt: 0.632 min).

Example 300N-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-5-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) (0.5 g,1.02 mmol) using the procedures of Example 297 to give the title productin 16% yield (15 mg). ¹H NMR (300 MHz, CD₃OD): δ 9.01 (s, 1H), 8.73 (s,1H), 8.01 (s, 1H), 7.88-7.86 (d, 1H), 7.71-7.70 (m, 1H), 7.65-7.56 (m,4H), 7.51-7.5 (m, 1H), 7.13-7.09 (m, 2H), 3.91 (s, 3H), 3.28-3.22 (m,2H), 1.38-1.35 (t, 3H); LC-MS (ESI): Calculated mass: 493.53; Observedmass: 493.9 [M+H]⁺ (rt: 1.232 min).

Example 301N-(3-(3-fluoropyridin-2-yl)-5-(5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)methanesulfonamide

The title compound was prepared from the title compound of Example294(f) using the procedures of Example 294(i). ¹H NMR (400 MHz,DMSO-d₆): δ 10.43 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H),7.99 (s, 1H), 7.95 (s, 1H), 7.94-7.88 (m, 1H), 7.86 (s, 1H), 7.67-7.65(m, 1H), 7.61-7.57 (m, 2H), 4.26-4.23 (t, 2H), 3.57-3.55 (t, 4H),2.77-2.67 (t, 2H), 2.43 (m, 4H), 2.13 (s, 3H): LC-MS (ESI): Calculatedmass: 525.58; Observed mass: 526.3 [M+H]⁺ (rt: 0.11 min).

Example 302N-(5-(5-(4-acetamido-1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of compound of Example 1(h) (120 mg, 0.271 mmol) in DMF(20 ml) were added N-(1H-pyrazol-4-yl)acetamide (50 mg, 0.407 mmol, 1.5eq), copper(I) oxide (4.9 mg, 0.027 mmol, 0.1 eq) and cesium carbonate(176 mg, 0.5429 mmol, 2.0 eq) and then heated at 110° C. for 48 h. Themixture was quenched and extracted as in Example 1(d). The solvent wasdistilled off to afford the crude residue which was purified bypreparative HPLC to yield the title product in 12.8% yield (16 mg). ¹HNMR (400 MHz, DMSO-d₆): δ 10.41 (s, 1H), 10.15 (s, 1H), 8.85 (s, 1H),8.54 (s, 1H), 8.14 (d, 1H), 8.07 (t, 1H), 7.87-7.71 (m, 5H), 7.53 (s,1H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 2.11 (s, 3H), 2.02 (s, 3H),LC-MS (ESI): Calculated mass: 461.54; Observed mass: 462.1 [M+H]⁺ (rt:0.7 min).

Example 303 Ethyl2-(4-(3-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-1-yl)acetate

The title compound was prepared from the title compound of Example131(c) using the procedures of Example 131(d). ¹H NMR (400 MHz,DMSO-d₆): 8.71 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.93(s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (s, 1H),7.48-7.42 (m, 1H), 7.29-7.24 (dt, 1H), 5.48 (s, 2H), 4.25-4.19 (q, 2H),2.13 (s, 3H), 1.27-1.24 (t, 3H): LC-MS (ESI): Calculated mass: 517.49;Observed mass: 518.4 [M+H]⁺ (rt: 1.37 min).

Example 304 N-(4′-fluoro-5-(6-(thiazol-2-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution ofN-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide(300 mg, 0.705 mmol) in THF (8 ml) was degassed by N₂ bubbling for 5min. Thiazol-2-yl zinc(II) bromide (485 mg, 2.11 mmol, 3.0 eq.) wasadded and the mixture was degassed for another 5 min. Pd(dppf)Cl₂ (57mg, 0.070 mmol, 0.1 eq.) aqueous sodium carbonate were added and theprocedure of Example 1(d) was followed. The crude residue of the productwas purified by preparative HPLC to yield the title product in 40% yield(120 mg) ¹H NMR (400 MHz, DMSO-D6): δ10.43 (s, 1H), 8.78 (s, 1H), 8.45(s, 1H), 8.08 (s, 1H), 8.01 (d, 1H), 7.94 (d, 1H), 7.85-7.73 (m, 4H),7.55 (s, 1H), 7.45 (t, 1H), 7.27 (t, 1H), 2.13 (s, 3H), LC-MS (ESI):Calculated mass: 429.47; Observed mass: 430.00 [M+H]⁺ (rt: 1.33 min).

Example 305N-(2′,4′-difluoro-5-(5-(thiazol-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared using the procedure of Example 304 startingfrom the compound of Example 208(a) to give the product in 10.4% yield(12 mg). ¹H NMR (400 MHz, DMSO-D6): 610.31 (s, 1H), 8.80 (s, 1H), 8.35(s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.83-7.75 (m, 3H), 7.61 (s, 1H),7.57 (d, 1H), 7.49-7.43 (m, 2H), 7.28 (dt, 1H), 3.19 (s, 3H), LC-MS(ESI): Calculated mass: 482.53; Observed mass: 483.2.

Example 306N-(2′,4′-difluoro-5-(5-(thiazol-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedure of Example 304 to give the product in 9.6% yield (15 mg). ¹HNMR (400 MHz, DMSO-D6): 610.35 (s, 1H), 8.81 (s, 1H), 8.35 (s, 1H), 8.01(d, 1H), 7.93 (s, 1H), 7.81-7.76 (m, 3H), 7.58 (d, 2H), 7.49-7.44 (m,2H), 7.29 (t, 1H), 3.30 (q, 2H), 1.26 (t, 3H), LC-MS(ESI): Calculatedmass: 496.55; Observed mass: 497.0 [M+H]⁺ (rt: 1.12 min).

Example 307N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 208(a) using theprocedure of Example 208(b) and1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleto afford the product in 9% yield (18 mg). ¹H NMR (300 MHz, DMSO-d₆): δ10.28 (s, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H),7.77 (d, 1H), 7.70-7.61 (m, 2H), 7.60-7.51 (m, 2H), 7.50-7.38 (m, 2H),7.30-7.29 (m, 1H), 4.60-4.40 (m, 1H), 3.15 (s, 3H), 1.44 (d, 6H); LC-MS(API): Calculated mass: 507.15; Observed mass: 508.0 [M+H]⁺ (rt: 1.00min).

Example 308N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedure of Example 200(c). ¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (s, 1H),8.64 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.75 (q, 1H),7.65 (q, 2H), 7.56 (m, 2H), 7.46 (m, 2H), 7.27 (m, 1H), 4.51 (m, 1H),3.28 (q, 2H), 1.46 (d, 6H), 1.25 (t, 3H). LC-MS (ESI): Calculated mass:521.17; Observed mass: 522.1 [M+H]⁺ (rt: 1.55 min).

Example 309N-(2′,4′-difluoro-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

A solution ofN-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide(0.2 g, 0.405 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N₂bubbling for 5 min.1-Isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.191 g, 0.810 mmol, 2.0 eq.) was added and the mixture was degassedfor another 5 min. Pd(dppf)Cl₂ (0.032 g, 0.040 mmol, 0.1 eq.) andaqueous sodium carbonate (0.17 g, 1.012 mmol, 2.5 eq.) were added andthe procedure of Example 1(d) was followed. The crude residue of theproduct was purified by column chromatography (60-120 silica gel, 80%ethyl acetate in hexane) to yield the product in 52.1% yield (0.11 g).¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.94 (s, 1H), 8.75 (d, 1H),8.44-8.42 (dd, 2H), 8.05 (s, 1H), 7.95 (s, 1H), 7.77-7.70 (m, 2H),7.48-7.43 (m, 2H), 7.30-7.26 (m, 1H), 4.54-4.51 (m, 1H), 4.13-4.11 (m,1H); 3.28-3.26 (m, 2H), 3.17-3.16 (d, 1H), 1.48-1.46 (d, 6H), 1.28-1.25(t, 3H), LC-MS (ESI): Calculated mass: 522.57 Observed mass: 523.0[M+H]⁺ (rt: 1.52 min).

Example 310N-(5-(5-(6-aminopyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The title compound was prepared from the title compound of Example208(a) using the procedures of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ10.43 (s, 1H), 9.05 (s, 1H), 8.42 (s, 2H), 8.17 (s, 2H), 7.84 (s, 1H),7.78-7.73 (m, 3H), 7.62 (m, 2H), 7.49 (m, 2H), 7.31-7.27 (m, 1H),7.15-7.12 (m, 1H), 3.19 (s, 3H); LC-MS (ESI): Calculated mass: 491.12;Observed mass: 492.2 [M+H]⁺ (rt: 0.28 min).

Example 311N-(5-(5-(6-aminopyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedures of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H),8.75 (s, 1H), 8.38-8.36 (m, 2H), 8.12 (s, 1H), 7.80-7.42 (m, 3H),7.72-7.66 (m, 2H), 7.58-7.57 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.27 (m,1H), 7.06-7.02 (m, 1H), 3.29 (quartet, 2H), 1.26 (s, 3H); LC-MS (ESI):Calculated mass: 505.14; Observed mass: 506.3 [M+H]⁺ (rt: 0.37 min).

Example 3121-(5-Acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carboxamidea)1-(5-Amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carboxamide

To a solution ofN-(5-(5-cyano-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(0.5 g, 1.28 mmol, 1 eq.) in ethanol (10 ml) was added 20% aqueoussolution of potassium hydroxide (0.721 g, 12.88 mmol, 10 eq.) and themixture was heated at 85° C. for 5 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordtitle product in 71% yield (0.32 g). LC-MS (ESI): Calculated mass:364.11; Observed mass: 365.1 [M+H]⁺ (rt: 0.59 min).

b)1-(5-Acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carboxamide

Acetic anhydride (0.1 ml, 1 vol.) was added dropwise at 0° C. to thecompound of Example 312(a) (0.1 g). The mixture was stirred for 30 minat RT and subsequently quenched by the addition of crushed ice. Theprecipitate formed was filtered and was washed with cold water to obtainoff-white solid. The solid was dried under vacuum to give the product in28.8% yield (32 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 8.80(s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.99-7.97 (d, 1H), 7.88 (s, 1H),7.80-7.76 (m, 2H), 7.57 (s, 1H), 7.49 (t, 1H), 7.41 (s, 1H), 7.31-7.29(t, 1H), 2.18 (s, 3H); LC-MS (ESI): Calculated mass: 406.12; Observedmass: 407.2 [M+H]⁺ (rt: 0.47 min).

Example 313N-(2′,4′-difluoro-5-(5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamidea)N-(5-((4-cyano-2-nitrophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A solution of N-(5-aminobiphenyl-3-yl)acetamide (1.5 g, 5.72 mmol),4-fluoro-3-nitrobenzonitrile (0.95 g, 5.72 mmol, 1.0 eq.) and potassiumfluoride (0.33 g, 5.72 mmol, 1.0 eq.) in DMF (15 ml) was heated at 130°C. for 12 h. The mixture was quenched and extracted as in Example 1(d).The solvent was distilled off to afford the crude residue which waspurified by column chromatography (60-120 silica gel, 50% ethyl acetatein hexane) to yield the title product in 43% yield (1 g).

b)N-(5-((2-amino-4-cyanophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-acetamide

To a solution of the compound of Example 313(a) (1.0 g, 2.45 mmol) inTHF (15 ml) were added a solution of ammonium chloride (0.52 g, 9.8mmol, 4 eq.) in water (5 ml) and zinc (0.64 g, 9.8 mmol, 4 eq.). Themixture was stirred at 45° C. for 2 h and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the title product in 86% yield (0.8 g).

c)N-(5-(5-cyano-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-acetamide

A mixture of the compound of Example 313(b) (0.8 g, 2.11 mmol) andformic acid (10 ml) was heated at 100° C. for 4 h. The formic acid wasdistilled off and the crude was dissolved in ethyl acetate. The ethylacetate layer was washed with water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the crude residue in97% yield (0.8 g).

d)N-(2′,4′-difluoro-5-(5-(N-hydroxycarbamimidoyl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 313(c) (0.1 g, 0.25 mmol) inethanol was added hydroxylamine hydrochloride (20 mg, 0.28 mmol, 1.1eq.) and Et₃N (0.1 ml, 0.75 mmol, 3 eq.) and the mixture was heated at80° C. for 3 h. The volatiles were distilled off and the crude solidobtained was washed several times with diethyl ether to afford the titlecompound in 100% yield (0.11 g).

e)N-(2′,4′-difluoro-5-(5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 313(d) (0.1 g, 0.237 mmol) inTFA (1 ml) was added trimethylortho acetate (5 ml) and the mixture washeated at 100° C. for 4 h. The volatiles were distilled off and thecrude product obtained was extracted with ethyl acetate and water anddried over sodium sulphate and the residue was purified by preparativeHPLC to give the pure product in 6.6% yield (6.6 mg). LC-MS (ESI):Calculated mass: 445.14; Observed mass: 446.1 [M+H]⁺ (rt: 1.15 min).

Example 314 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-2-(3, 5-dimethylpiperazin-1-yl)acetamide

The compound was prepared from the compound of Example 132(a) (60 mg,0.149 mmol) using the procedure of Example 225 and2-(3,5-dimethylpiperazin-1-yl)acetic acid (30 mg, 0.179 mmol, 1.2 eq) togive the product in 21.9% yield (18 mg). LC-MS (ESI): Calculated mass:556.25; Observed mass: 557.2 [M+H]⁺ (rt: 0.67 min).

Example 315N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,3′-dihydro-[1,1′-biphenyl]-3-yl)-2-(4-ethylpiperazin-1-yl)acetamide

The compound was prepared fromN-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(4-ethylpiperazin-1-yl)acetamide(300 mg, 0.540 mmol) using the method of Example 1(i) to give theproduct in 11.6% yield (35 mg). NMR (400 MHz, DMSO-D6): δ 9.40 (brs,1H), 8.96 (s, 1H), 8.740 (d, 1H), 8.44 (d, 1H), 8.38 (s, 1H), 8.33 (s,1H), 8.07 (s, 1H), 8.97 (s, 1H), 7.794-7.713 (m, 2H), 7.48 (t, 1H), 7.31(t, 1H), 3.93 (s, 3H), 3.44 (s, 2H), 3.19-3.12 (m, 8H), 2.71 (q, 2H),1.24 (t, 3H), LC-MS (ESI): Calculated mass: 558.6; Observed mass: 557.0[M−H]⁻ (rt: 0.21 min).

Example 316 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-(4-methylpiperazin-1-yl)acetamide

The compound was prepared from the compound of Example 132(a) (75 mg,0.186 mmol) using the procedure of Example 225 and2-(4-methylpiperazin-1-yl)acetic acid (44.2 mg, 0.279 mmol, 1.5 eq) togive the product in 34.6% yield (35 mg). ¹H NMR (400 MHz, DMSO-d₆): δ10.29 (s, 1H), 8.94 (s, 1H), 8.72 (d, 1H), 8.42-8.31 (d, 3H), 8.05 (s,1H), 7.93 (s, 1H), 7.77-7.71 (m, 2H), 7.49-7.43 (m, 1H), 7.29 (t, 1H),3.90 (s, 3H), 3.17-3.11 (m, 4H), 2.80 (s, 3H), 2.67 (m, 2H), 2.50 (m,4H); LC-MS (ESI): Calculated mass: 542.58; Observed mass: 543.1 [M+H]⁺(rt: 0.252 min).

Example 3171-Cyclopentyl-3-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo-[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)urea

To a solution of the compound of Example 132(a) (65 mg, 0.1616 mmol) inDCM was added diisopropylamine (89 mg, 0.485 mmol, 3 eq) and cyclopentylisocyanate (19.7 mg, 0.1778 mmol, 1.1 eq). The mixture was stirred for16 h, and quenched and extracted as in Example 2(b). The solvent wasdistilled off to give the crude residue which was purified bypreparative HPLC to give the product in 12% yield (10 mg). ¹H NMR (400MHz, DMSO-d₆): 68.92 (s, 1H), 8.71 (t, 1H), 8.41 (d, 1H), 8.30 (s, 1H),8.05 (t, 1H), 7.72-7.66 (m, 1H), 7.56 (s, 1H), 7.46-7.40 (m, 1H),7.27-7.24 (m, 2H), 6.30 (s, 1H), 3.93 (s, 3H), 3.10 (m, 1H), 1.87-1.81(m, 2H), 1.65-1.53 (m, 4H), 1.43-1.37 (m, 2H); LC-MS (ESI): Calculatedmass: 513.54; Observed mass: 514.5 [M+H]⁺ (rt: 1.56 min).

Example 318N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-(piperazin-1-yl)acetamide a)tert-butyl4-(2-((2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

The compound was prepared from the compound of Example 132(a) (120 mg,0.298 mmol) using the method of Example 225 and2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (145 mg, 0.597mmol, 2 eq) to give the product in 10.6% yield (20 mg). LC-MS (ESI):Calculated mass: 628; Observed mass: 629.1 [M+H]⁺ (rt: 1.056 min).

b) N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-2-(piperazin-1-yl)acetamide

To a solution of the compound of Example 318(a) (12 mg, 0.0191 mmol) inDCM was added TFA (1 ml) and the mixture was stirred at RT for 16 h. Themixture was concentrated to give the product in 98% yield (10 mg). ¹HNMR (400 MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.93 (s, 1H), 8.70 (d, 2H),8.41-8.07 (d, 1H), 8.35 (t, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.94-7.93(d, 1H), 7.76-7.68 (m, 2H), 7.47-7.42 (m, 1H), 7.30-7.25 (m, 1H), 3.89(s, 3H), 3.50 (s, 2H), 3.21 (s, 4H), 2.92 (s, 4H); LC-MS (ESI):Calculated mass: 528.22; Observed mass: 529.2[M+H]⁺ (rt: 0.182 min).

Example 319 N-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-3-yl)-[1, 1′-biphenyl]-3-yl)-1-methylpiperidine-4-carboxamide

The compound was prepared from the compound of Example 132(a) (75 mg,0.1865 mmol) using the method of Example 225 and1-methylpiperidine-4-carboxylic acid (40 mg, 0.27 mmol, 1.5 eq) to givethe product in 15% yield (15 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.97 (s,1H), 8.67 (s, 1H), 8.31 (t, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.93 (s,1H), 7.81 (t, 1H), 7.74 (s, 1H), 7.65-7.59 (m, 1H), 7.13-7.07 (m, 2H),3.96 (s, 3H), 3.66-3.63 (m, 2H), 3.14-3.07 (m, 2H), 2.92 (s, 3H),2.79-2.73 (m, 1H), 2.24-2.01 (m, 4H); LC-MS (ESI): Calculated mass:527.22; Observed mass: 528.0 [M+H]⁺ (rt: 0.20 min).

Example 320 N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,3′-dihydro-[1,1′-biphenyl]-3-yl)-2-(4-ethylpiperazin-1-yl)acetamide

The compound was prepared from the compound of Example 132(a) (100 mg,0.249 mmol) using the procedure of Example 225 and2-(4-ethylpiperazin-1-yl)acetic acid (85 mg, 0.498, mmol, 2.0 eq.) togive the product in 38% yield (40 mg).

Example 321N-(5-(5-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution of the compound ofN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(110 mg, 0.198 mmol) in DMSO was added potassium carbonate (54 mg, 0.391mmol, 2.0 eq.). The mixture was degassed by N₂ bubbling for 10 minfollowed by addition of 1-ethylpiperazine (68 mg, 0.595 mmol, 3.0 eq.)and L-proline (4.5 mg) and CuI (3 mg). Then seal tube was closed and themixture was kept at 95° C. for 24 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to affordthe crude residue which was purified by preparative HPLC to give theproduct in 18% yield (20 mg). ¹H NMR (400 MHz, DMSO-D6): 610.3 (s, 1H),8.98 (s, 1H), 7.77 (m, 1H), 7.66 (s, 1H), 7.60 (brs, 2H), 7.50 (brs,2H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 3.60 (m, 4H), 3.29-3.20 (m, 4H),3.02 (q, 2H), 2.90 (t, 1H), 1.30 (t, 3H), 1.04 (q, 4H), LC-MS (ESI):Calculated mass: 537.62; Observed mass: 538.1 [M+H]⁺

Example 322N-(2′,4′-difluoro-5-(5-(3-hydroxypyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,3′-dihydro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared as in Example 321 using (S)-pyrrolidin-3-ol togive the pure product in 12% yield (12 mg). NMR (400 MHz, DMSO-D6): δ8.52 (s, 1H), 7.77 (q, 1H), 7.56 (d, 3H), 7.51-7.46 (m, 2H), 7.29 (t,1H), 6.82 (s, 1H), 6.73 (d, 1H), 5.01 (d, 1H), 4.45 (s, 1H), 3.52 (q,1H), 3.35 (s, 1H), 3.14 (d, 1H), 2.87 (q, 1H), 2.12-2.09 (m, 1H),1.96-1.94 (m, 1H), 1.03 (d, 4H), LC-MS (ESI): Calculated mass: 512.1;Observed mass: 510 [M−H]⁻ (rt: 0.42 min).

Example 323N-(5-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The title compound was prepared from the title compound of Example200(b) using the procedures of Example 1(i). ¹H NMR (400 MHz, CD₃OD): δ8.51 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.68-7.62 (m,3H), 7.58 (d, 1H), 7.51 (dd, 2H), 7.15-7.10 (m, 2H), 4.75-4.72 (m, 1H),3.24 (quartet, 2H), 2.23-2.19 (m, 2H), 2.06-2.01 (m, 2H), 1.94-1.90 (m,2H), 1.77-1.73 (m, 2H), 1.36 (t, 2H); LC-MS (ESI): Calculated mass:547.19; Observed mass: 548.1 [M+H]⁺ (rt: 1.66 min).

Example 324N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0eq.) followed by ethanesulfonyl chloride (76 mg, 0.66 mmol, 2.0 eq.).The mixture was stirred for 1 h, and quenched and extracted as inExample 2(b). The solvent was distilled off to afford the crude residuewhich was taken to the next step without further purification, yield76.68% (125 mg); LC-MS (ESI): Calculated mass: 492.01; Observed mass:493.0 [M+H]⁺ (rt: 1.72 min).

b)N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 324(a) (125 mg,0.25 mmol) using the method of Example 200(c) and1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(136 mg, 0.50 mmol, 2.0 eq.) to give the product in 21.73% yield (30mg). ¹H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.96 (s, 1H), 8.76-8.75(d, 1H), 8.45-8.42 (t, 2H), 8.06 (s, 1H), 7.95-7.94 (t, 1H), 7.77-7.70(m, 2H), 7.49-7.43 (m, 2H), 7.28 (t, 1H), 4.74-4.70 (t, 1H), 3.31-3.26(q, 2H), 2.14-2.09 (m, 2H), 2.00-1.95 (m, 2H), 1.84-1.81 (m, 2H),1.68-1.65 (m, 2H), 1.28-1.24 (t, 3H); LC-MS (ESI): Calculated mass:548.18; Observed mass: 549.1 [M+H]⁺ (rt: 1.70 min).

Example 3252-(4-(1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)ethanol

To a solution ofN-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide(0.12 g, 0.125 mmol) in methanol (5 ml) was added (1 ml) acetyl chlorideat 0° C. The mixture was stirred at RT for 16 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the product in 28% yield (0.026 g). ¹H NMR (400 MHz, DMSO-d₆):δ 8.53 (s, 1H), 8.20 (s, 1H), 7.97-7.95 (d, 2H), 7.69-7.64 (m, 2H),7.59-7.56 (dd, 1H), 7.39-7.36 (m, 1H), 6.88 (s, 2H), 6.82 (d, 1H), 5.70(s, 2H), 4.95 (s, 1H), 4.19-4.16 (t, 2H), 3.81-3.78 (t, 2H); LC-MS(ESI): Calculated mass: 431.44; Observed mass: 432.2 [M+H]⁺ (rt: 0.4min).

Example 326N-(5-(5-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the title compound of Example 1(h) usingthe procedures of Example 1(i). ¹H NMR (400 MHz, DMSO-d₆): δ 10.43 (s,1H), 9.0 (s, 1H), 8.17 (s, 2H), 8.13 (m, 1H), 8.06 (s, 1H), 7.82 (s,1H), 7.74-7.73 (m, 3H), 7.55 (s, 1H), 7.5-7.42 (m, 1H), 7.3-7.26 (dt,1H), 2.12 (s, 3H): LC-MS (ESI): Calculated mass: 429.42; Observed mass:429.8 [M+H]⁺ (rt: 0.6 min).

Example 327N-(5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The title compound was prepared from the title compound of Example 1(h)using the procedures of Example 1(i).

Example 328 N-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(1H-1,2, 4-triazol-1-yl) acetamide a)N-(5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) (2 g, 4.5mmol) using the procedures of Example 200(c) and2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine(1.68 g, 5.4 mmol, 1.2 eq) to yield the product in 50% yield (1.2 g).LC-MS (ESI): Calculated mass: 548.2; Observed mass: 549.4 [M+H]⁺ (rt:0.302 min).

b) 5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′, 4′-difluoro-[1,1′-biphenyl]-3-amine

The compound was prepared from the compound of Example 328(a) (1.1 g,2.00 mmol) using the procedure of Example 2(a) to afford the product in50% yield (0.7 g).

c)N-(5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide

The compound was prepared from the compound of Example 328(b) (100 mg,0.1984 mmol) using the procedure of Example 225 to give the product in65% yield (80 mg). LC-MS (ESI): Calculated mass: 613; Observed mass: 614[M+H]⁺ (rt: 1.681 min).

d) N-(2′, 4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(1H-1, 2, 4-triazol-1-yl) acetamide

The solution of the compound of Example 328(c) (60 mg, 0.0975 mmol) inTFA was heated at 50° C. for 16 h. The mixture was concentrated to givethe product in 50% yield (30 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s,1H), 8.61 (s, 1H), 8.11 (s, 1H), 8.04-7.94 (m, 3H), 7.81-7.75 (m, 4H),7.63 (d, 2H), 7.49-7.44 (m, 1H), 7.28 (t, 1H), 6.46 (d, 1H), 5.24 (s,2H), LC-MS (ESI): Calculated mass: 523.16; Observed mass: 524.1 [M+H]⁺(rt: 0.343 min).

Example 3291-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)ureaa)1-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(75 mg, 0.148 mmol) in DCM was added furfuryl isocyanate (19 mg, 0.163mmol, 1.1 eq.). The mixture was stirred overnight and quenched and andextracted as in Example 2(b). The solvent was distilled off to affordthe crude residue which was recrystallized in ether to afford the titlecompound in 86% yield (80 mg).

b)1-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 329(a) (80 mg) in THF (5 ml)and ethanol (5 ml) was added 10% palladium on carbon (10 mg) followed by20% palladium hydroxide (10 mg). The mixture was stirred under hydrogenatmosphere for 2 h. The reaction mass was filtered through a bed ofcelite and concentrated to afford the crude product which was purifiedby silica gel (60-120) column chromatography using 6% MeOH in chloroformas eluant to afford the product in 58% yield (40 mg).

Example 330 N-(2′,4′-difluoro-5-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methane sulfonamide

To a solution ofN-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide(0.15 g, 0.252 mmol) in methanol (5 ml) was added acetyl chloride (1 ml)at 0° C. as in Example 1(d). The solvent was distilled off to afford theproduct (0.063 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.22 (s,1H), 8.00-7.97 (d, 2H), 7.80-7.69 (m, 2H), 7.67-7.61 (m, 1H), 7.59-7.60(d, 1H), 7.53 (s, 2H), 7.47-7.41 (m, 2H), 7.29-7.25 (t, 1H), 4.97-4.95(t, 1H), 4.18-4.15 (m, 2H), 3.80-3.78 (m, 2H), 3.14 (s, 3H) Calculatedmass: 509.1; Observed mass: 510.3 [M+H]⁺ (rt: 1.18 min).

Example 331N-(2′,6′-difluoro-5-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]-pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamidea) tert-butyl4-(4-(3-(5-acetamido-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The title compound was prepared from the title compound of Example209(c) using the procedures of Example 209(d).

b)N-(2′,6′-difluoro-5-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

A solution of the compound of Example 331(a) (180 mg, 0.293 mmol) in TFAwas stirred at RT for 16 h. The mixture was concentrated to give thecrude product which was purified by preparative HPLC to afford theproduct in 13% yield (20 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.41 (s,1H), 8.87 (s, 1H), 8.77-8.76 (d, 1H), 8.7-8.5 (br, 1H), 8.42 (s, 1H),8.36 (m, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.55 (m, 1H),7.31-7.27 (t, 2H), 4.58-4.44 (m, 1H), 3.17-3.09 (m, 4H), 2.32-2.16 (m,4H), 2.11 (s, 3H) Calculated mass: 513.54; Observed mass: 514.3 [M+H]⁺(rt: 1.32 min).

Example 3321-(5-Acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carboxylicacid a) Methyl4-((5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)amino)-3-nitrobenzoate

A solution of N-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide(1.0 g, 3.813 mmol), methyl 4-fluoro-3-nitrobenzoate (0.835 g, 4.194mmol, 1.1 eq.) and potassium fluoride (0.265 g, 4.457 mmol, 1.2 eq.) inDMF was heated at 130° C. for 16 h. The mixture was quenched andextracted as in Example 1(d). The solvent was distilled off to give thecrude residue which was purified by column chromatography (60-120 silicagel, 40% ethyl acetate in hexane) to give the product in 48.78% yield(0.82 g).

b) Methyl1-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]-imidazole-5-carboxylate

The compound was prepared from the compound of Example 332(a) using themethods of Example 1(g) and 1(h) to give the product in 91.3% yield(0.58 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.89 (s, 1H), 8.38(s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.86-7.83 (d, 2H), 7.79-7.75 (m,2H), 7.53 (s, 2H), 7.26-7.25 (m, 1H), 2.10 (s, 3H); LC-MS (ESI):Calculated mass: 421.4; Observed mass: 422 [M+H]⁺ (rt: 1.52 min).

c)1-(5-Acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of the compound of Example 332(b) (0.1 g, 0.24 mmol, 1eq.) in THF (10 ml), methanol (6 ml) and water (4 ml) was added LiOH(0.049 g, 1.18 mmol, 5 eq.) The mixture was stirred at RT overnight. Thereaction mass was diluted with water and extracted as in Example 1(d).The solvent was distilled off to afford the product in 26% yield (0.025g). ¹H NMR (400 MHz, DMSO-d₆): δ 12.92 (s, 1H), 10.38 (s, 1H), 8.79 (s,1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.98-7.96 (d, 1H), 7.87 (s, 1H),7.78-7.73 (m, 2H), 7.52-7.41 (m, 2H), 7.28-7.24 (t, 1H), 2.11 (s, 3H);LC-MS (ESI): Calculated mass: 407.11; Observed mass: 408.4 [M+H]⁺ (rt:1.01 min).

Example 333N-(5-(5-(4-bromo-1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 70 (4 g, 9.73 mmol) in aceticacid (40 ml) bromine (1.53 g, 9.73 mmoles) in acetic acid (10 ml) wasadded dropwise at RT. The reaction was stirred at RT for 1 h, cold waterwas added and the solid obtained was filtered and dried to afford thetitle product in 63.15% yield (3 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42(s, 1H), 8.88 (s, 2H), 8.24 (s, 1H), 8.23 (s, 1H), 8.0 (s, 1H),7.92-7.85 (m, 3H), 7.85-7.78 (m, 3H), 7.66 (s, 1H), 7.4-7.3 (m, 2H),2.13 (s, 3H); LC-MS (ESI): Calculated mass: 490.33; Observed mass: 491.7[M+H]⁺ (rt: 1.66 min).

Example 334N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamidea)N-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

To a solution of5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0eq.) followed by methanesulfonyl chloride (76 mg, 0.66 mmol, 2 eq.). Thereaction was stirred for 1 h, and quenched and extracted as in Example2(b). The solvent was distilled off to afford the crude residue whichwas taken next step without further purification. Yield 75.0% (120 mg).¹H NMR (300 MHz, DMSO-d₆): δ 10.30 (s, 1H), 9.30 (s, 1H), 8.56 (s, 1H),7.83 (s, 1H), 7.45 (s, 1H), 7.44 (s, 2H), 3.16 (s, 3H); LC-MS (ESI):Calculated mass: 479.5; Observed mass: 480.2 [M+H]⁺ (rt: 1.59 min).

b)N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 334(a) (0.120 g,0.25 mmol) using the procedure of Example 200(c) and1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.253 g, 0.50 mmol, 2.0 eq) to afford the crude residue which waspurified by preparative HPLC to give the product 19% yield (0.026 g). ¹HNMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.96 (s, 1H), 8.75 (d, 1H),8.44-8.41 (d, 2H), 8.05 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.74-7.72(m, 1H), 7.46-7.41 (m, 2H), 7.28 (t, 1H), 4.74-4.70 (t, 1H), 3.17 (s,3H), 2.14-2.09 (m, 2H), 2.00-1.95 (m, 2H), 1.84-1.80 (m, 2H), 1.68-1.65(m, 2H); LC-MS (ESI): Calculated mass: 534.16; Observed mass: 535.1[M+H]⁺ (rt: 1.70 min).

Example 335N-(5-(6-(1-cyclopentyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared using the procedures of Example 334 startingfrom5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(133 mg, 0.33 mmol) and using cyclopropanesulfonyl chloride (20 mg, 0.66mmol, 2.0 eq.) and1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.115 g, 0.43 mmol, 2.0 eq.) to give the crude residue which waspurified by preparative HPLC to give the product in 27.86% yield (34mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 8.96 (s, 1H), 8.76-8.75(d, 1H), 8.45-8.42 (t, 2H), 8.06 (s, 1H), 8.00-7.99 (d, 1H), 7.78-7.70(m, 2H), 7.49-7.43 (m, 2H), 7.31-7.26 (t, 1H), 4.74-4.70 (t, 1H), 2.84(m, 1H), 2.14-2.08 (m, 2H), 2.00-1.96 (m, 2H), 1.84-1.81 (m, 2H),1.69-1.65 (m, 2H), 1.09-1.02 (m, 4H), LC-MS (ESI): Calculated mass:560.18; Observed mass: 561.2 [M+H]⁺ (rt: 1.70 min).

Example 336N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-methoxyacetamide

The title compound was prepared from the compound of Example 2(a) usingthe procedures of Example 205. ¹H NMR (300 MHz, DMSO-d₆): δ 10.28 (s,1H), 8.99 (s, 1H), 8.23 (d, 2H), 8.03-7.98 (m, 3H), 7.80-7.67 (m, 3H),7.60 (s, 1H), 7.47 (t, 1H), 7.29 (t, 1H), 4.09 (s, 3H), 3.89 (s, 3H),3.42 (s, 2H); LC-MS (API): Calculated mass: 473.17; Observed mass: 474.1[M+H]⁺ (rt: 0.90 min).

Example 337N-(5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro[1,1′-biphenyl]-3-yl)ethanesulfonamidea)N-(2′,4′-difluoro-5-((2-nitro-4-(1H-pyrazol-3-yl)phenyl)amino)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 168(b) (0.8 g, 1.66 mmol) inethanol (15 ml) was added hydrazine (7 ml) and stirred at RT overnight.The mixture was purified by silica gel chromatography using 1% MeOH inchloroform as eluant to afford the product in 62% yield (0.46 g).

b)N-(5-((2-amino-4-(1H-pyrazol-3-yl)phenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 337(a) (0.46 g, 1.02 mmol) inTHF (3 ml) and methanol (3 ml) was added 10% palladium on carbon. Themixture was stirred under hydrogen atmosphere for 4 h. The mixture wasfiltered through a bed of celite and concentrated to afford the productin 66% yield (0.28 g).

c)N-(5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

A mixture of the compound of Exampe 337(b) (0.3 g, 0.69 mmol) and formicacid (3 ml) was heated at 80° C. for 2 h. The formic acid was distilledoff and the crude product was extracted with DCM. The solvent wasdistilled off to afford the product in 95% yield (0.3 g).

d)5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

A solution of the compound of Exampe 337(c) (0.26 g, 0.465 mmol) inethanol (3 ml) was added 1:1 HCl solution and heated at 80° C. for 1 h.The mixture was basified with saturated NaHCO₃ solution and extractedwith DCM (2×15 ml). The DCM layer was concentrated to afford the productin 80% yield (0.28 g).

e)N-(5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

To a solution of the compound of Exampe 337(d) (100 mg, 0.25 mmol) inDCM was added pyridine 0.2 ml followed by ethanesulfonyl chloride (33mg, 0.25 mmol, 1.0 eq.). The mixture was stirred for 1 h, quenched withwater and extracted with DCM (3×10 ml). The combined organic layer wasconcentrated and the crude material was stirred with 10% NaOH solution(3 ml) for 1 h and washed with water, brine and dried over sodiumsulphate. The aqueous layer was extracted with DCM (2×10 ml). Thesolvent was distilled to afford the crude material which was purified bypreparative HPLC to afford the title product. ¹H NMR (400 MHz, DMSO-d₆):δ 13-12.5 (brs, 1H), 10.4-10.2 (brs, 1H), 8.69 (s, 1H), 8.21 (s, 1H),7.87-7.86 (m, 1H), 7.79-7.71 (m, 3H), 7.56 (m, 2), 7.42-7.42 (m, 2H),7.3-7.25 (dt, 1H), 6.81 (d, 1H), 3.35-3.25 (q, 2H), 1.27-1.24 (t, 3H);LC-MS (API): Calculated mass: 479.5; Observed mass: 480.3 [M+H]⁺ (rt:1.32 min).

Example 338N-(5-(5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 208(a) using theprocedures of Example 208(b). ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (s, 1H),8.2 (s, 1H), 7.87-7.85 (m, 1H), 7.76-7.72 (m, 3H), 7.51-7.49 (m, 2H),7.44-7.4 (m, 2H), 7.3-7.22 (dt, 1H), 6.81-6.8 (d, 1H), 3.11 (s, 3H);LC-MS (API): Calculated mass: 465.48; Observed mass: 466.32 [M+H]⁺ (rt:1.4 min).

Example 339N-(5-(6-(6-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound of Example 334(a) using theprocedures of Example 246. ¹H NMR (300 MHz, CD₃OD): δ 8.73 (s, 1H), 8.56(s, 1H), 8.17 (d, 2H), 7.79-7.71 (m, 3H), 7.59-7.57 (m, 1H), 7.42 (m,1H), 7.08-7.03 (m, 2H), 6.65-6.62 (m, 1H), 3.04 (s, 3H); LC-MS (ESI):Calculated mass: 492.12; Observed mass: 493.0 [M+H]⁺ (rt: 0.20 min).

Example 340N-(2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine(70 mg, 0.175 mmol) using the procedure of Example 2(b) andethanesulfonyl chloride (26 mg, 0.21 mmol, 1.2 eq.) to give the pureproduct in 16.2% yield (14 mg). NMR (400 MHz, DMSO-D6): 610.35 (s, 1H),8.80 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.70 (d, 1H),7.65-7.60 (m, 4H), 7.51 (s, 2H), 7.49-7.39 (m, 1H), 3.88 (s, 3H), 3.30(q, 2H), 1.26 (t, 3H), LC-MS (ESI): Calculated mass: 493.53; Observedmass: 494.2 [M+H]⁺ (rt: 0.1.33 min).

Example 341 N-(5-(6-(2-aminopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl) methane sulfonamide

To a solution of tert-butyl(5-(3-(2′,4′-difluoro-5-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)carbamate(0.2 g, 0.33 mmol) in DCM (5 ml) was added TFA (1.2 ml) at 0° C. Themixture was stirred at RT for 16 h. The mixture was concentrated invacuum, quenched with sodium bicarbonate and extracted as in Example1(d). The solvent was distilled off to afford the product in 16.9% yield(0.28 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.30 (s, 1H), 9.04 (s, 1H), 8.73(s, 1H), 8.46 (s, 1H), 8.00 (d, 1H), 7.91 (s, 1H), 7.79 (m, 2H), 7.44(m, 2H), 7.30 (m, 1H), 6.95 (d, 1H), 6.82 (s, 1H), 6.06 (s, 2H), 3.17(s, 3H); LC-MS (ESI): Calculated mass: 492.50; Observed mass: 493.1[M+H]⁺ (rt: 0.39 min).

Example 342 N-(5-(5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-2-(pyrrolidin-1-yl) acetamide

The compound was prepared from the compound of Example 29(a) (75 mg,0.193 mmol) using the procedure of Example 225 and2-(pyrrolidin-1-yl)acetic acid (37.3 mg, 0.289 mmol, 1.5 eq.) to givethe product in 31.18% yield (30 mg). ¹H NMR (600 MHz, CD₃OD): δ 8.62 (s,1H), 8.29-8.28 (d, 1H), 8.17-8.16 (t, 1H), 8.12 (s, 1H), 7.85-7.83 (dd,3H), 7.77-7.76 (d, 1H), 7.68-7.67 (m, 1H), 7.59 (s, 1H), 7.15-7.12 (m,2H), 6.58-6.57 (t, 1H), 3.73 (s, 2H); 3.02 (t, 4H); 2.00-1.94 (m, 4H);LC-MS (ESI): Calculated mass: 498.53, Observed mass: 499.6 [M+H]⁺ (rt:0.6 min).

Example 343N-(5-(5-(2-aminopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)methane sulfonamide

The compound was prepared from5-(1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)pyridin-2-amine(50 mg, 0.121 mmol) using the method of Example 2(b) and methanesulfonylchloride (27.7 mg, 0.242 mmol, 2.0 eq) to give the product in 37.2%yield (22 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 8.84 (s, 1H),8.29 (s, 1H), 8.04-8.20 (d, 3H), 7.89-7.87 (d, 1H), 7.81-7.74 (m, 2H),7.61 (s, 1H), 7.57 (s, 1H), 7.47-7.44 (d, 2H), 7.39-7.38 (d, 1H),7.31-7.26 (m, 1H), 3.19 (s, 3H); LC-MS (ESI): Calculated mass: 491.51Observed mass: 492.2 [M+H]⁺ (rt: 0.24 min).

Example 344N-(5-(5-(4-amino-3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.46 (s, 1H),8.86 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.81-7.71 (m, 3H), 7.59 (d,1H), 7.51-7.40 (m, 3H), 7.33-7.24 (m, 2H), 6.88-6.82 (m, 1H), 5.25 (brs,2H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 472.15; Observed mass:473.5 [M+H]⁺ (rt: 1.47 min).

Example 345N-(5-(5-(2-aminopyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethane sulfonamide

The compound was prepared as in Example 343 using ethanesulfonylchloride (46.8 mg, 0.363 mmol, 2.0 eq.) to give the product in 36.1%yield (33 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 8.84 (s, 1H),8.29 (s, 1H), 8.04-7.99 (t, 3H), 7.88-7.86 (d, 1H), 7.81-7.73 (m, 2H),7.59-7.58 (d, 1H), 7.48-7.44 (m, 2H), 7.39-7.31 (d, 1H), 7.31-7.26 (m,2H), 3.32-3.27 (q, 2H), 1.28-1.24 (t, 3H), LC-MS (ESI): Calculated mass:505.54; Observed mass: 506.3 [M+H]⁺ (rt: 0.2 min).

Example 346 N-(5-(6-(2-aminopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl) ethanesulfonamide

The compound was prepared from tert-butyl(5-(3-(5-(ethylsulfonamido)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)carbamate(0.2 g, 0.33 mmol) following the procedure of Example 290 to afford theproduct in 17.9% yield (0.30 g). ¹H NMR (300 MHz, DMSO-d₆): δ 10.42 (s,1H), 9.01 (s, 1H), 8.85 (s, 1H), 8.64. (s, 1H), 7.96 (d, 1H), 7.81-7.73(m, 3H), 7.44-7.32 (m, 4H), 7.21 (m, 2H), 3.25-3.23 (q, 2H), 1.26-1.23(t, 3H), Calculated mass: 506.53; Observed mass: 507.3 [M+H]⁺ (rt: 0.2min).

Example 347N-(5-(6-(6-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The title compound was prepared as in Example 340 starting fromN-(5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide.¹H NMR (300 MHz, CD₃OD): δ 8.73 (s, 1H), 8.56 (s, 1H), 8.17 (d, 2H),7.79-7.71 (m, 3H), 7.59-7.57 (m, 1H), 7.42 (m, 1H), 7.08-7.03 (m, 2H),6.65-6.62 (m, 1H), 3.04 (s, 3H); LC-MS (ESI): Calculated mass: 492.12;Observed mass: 493.0 [M+H]⁺ (RT: 0.20 min).

Example 3481-(2′,4′-difluoro-5-(6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)urea

To a solution of the compound of Example 132(a) (60 mg, 0.149 mmol) inDCM was added DIPEA (0.1 ml, 0.447 mmol, 3 eq.) followed by2-(isocyanatomethyl)furan (22 mg, 0.179 mmol, 1.2 eq). The mixture wasstirred for 16 h, and quenched and extracted as in Example 2(b). Thesolvent was distilled off to afford the crude residue which was purifiedby preparative HPLC to give the product in 44.87% yield (35 mg). ¹H NMR(400 MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.92 (s, 1H), 8.71 (s, 1H), 8.4 (s,1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.72-7.67 (m, 2H), 7.60(d, 2H), 7.43 (t, 1H), 7.25 (t, 1H), 6.73 (t, 1H), 6.41 (s, 1H), 6.3 (d,2H), 4.3 (d, 2H), 3.90 (s, 3H); LC-MS (ESI): Calculated mass: 525.17;Observed mass: 526.3 [M+H]⁺ (rt: 1.49 min).

Example 349N-(2′,4′-difluoro-5-(5-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 203(a) using theprocedures of Example 203(b). ¹H NMR (400 MHz, DMSO-d6): δ 10.3 (s, 1H),8.96 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.77-7.66 (m,2H), 7.62 (s, 2H), 7.52-7.44 (m, 2H), 1.0 (s, 4H); LC-MS (ESI):Calculated mass: 505.14; Observed mass: 506.0 [M+H]⁺ (rt: 0.632 min).

Example 350N-(2′,4′-difluoro-5-(5-(pyridin-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the title compound of Example 203(a)using the procedures of Example 203(b). ¹H NMR (300 MHz, DMSO-d₆): δ8.62-8.59 (m, 3H), 8.18 (s, 1H), 7.84-7.81 (m, 4H), 7.67-7.56 (m, 4H),7.15-7.1 (m, 2H), 2.7 (m, 1H), 1.2-1.1 (m, 4H); LC-MS (API): Calculatedmass: 502.54; Observed mass: 503.2 [M+H]⁺ (rt: 1.15 min).

Example 3511-(5-(Cyclopropanesulfonamido)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo-[d]imidazole-5-carboxamide

The compound was prepared from the compound of Example 312(a) (100 mg,0.27 mmol) using the procedure of Example 2(b) and cyclopropanesulfonylchloride (42 mg, 0.30 mmol, 2.0 eq.) to give the product in 27.34% yield(35 mg). ¹H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.82 (s, 1H), 8.37(s, 1H), 8.08 (s, 1H), 7.96-7.94 (d, 1H), 7.77-7.72 (m, 2H), 7.60-7.58(d, 2H), 7.51 (s, 1H), 7.48-7.43 (m, 1H), 7.38 (s, 1H), 7.29-7.24 (m,1H), 2.89-2.86 (t, 1H), 1.02-1.01 (d, 4H); LC-MS (ESI): Calculated mass:468.11; Observed mass: 469.1 [M+H]⁺ (rt: 1.23 min).

Example 352 N-(2′,4′-difluoro-5-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazo-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(0.15 g, 0.242 mmol) using the procedure of Example 330 to give theproduct in 78% yield (0.063 g). ¹H+NMR (400 MHz, DMSO-d₆): δ 10.15 (s,1H), 8.65 (S, 1H), 8.22 (s, 1H), 8.00-7.97 (d, 2H), 7.75 (s, 1H),7.76-7.62 (d, 2H), 7.56 (m, 2H), 7.47 (s, 3H), 7.27 (s, 1H), 4.95 (s,1H), 4.17 (s, 1H), 3.79 (s, 1H), 1.01 (m, 5H); LC-MS (ESI): Calculatedmass: 535.57; Observed mass: 536.4[M+H]⁺ (rt: 1.0 min).

Example 353N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-N,N-dimethylsulfuricdiamide

The compound was prepared from the title compound of Example 210(a)using the procedures of Example 210(b). ¹H NMR (300 MHz, CD₃OD): δ 9.4(s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.78-7.67 (m, 3H),7.55-7.46 (m, 4H), 7.06-7.03 (d, 2H), 3.86 (s, 3H), 2.77 (s, 6H); LC-MS(ESI): Calculated mass: 508.54; Observed mass: 509.0 [M+H]⁺ (rt: 0.96min).

Example 354N-(2′,4′-difluoro-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the title compound of Example 131(c)using the procedures of Example 131(d). ¹H NMR (400 MHz, DMSO-d₆): δ13.0 (br, 1H), 10.2 (br, 1H), 8.69 (s, 1H), 8.20 (s, 1H), 7.87-7.71 (m,4H), 7.56 (m, 2H), 7.48-7.42 (s, 1H), 7.3-7.25 (dt, 1H), 6.81 (d, 1H),3.35-3.25 (q, 2H), 1.27-1.24 (t, 3H): LC-MS (ESI): Calculated mass:479.5; Observed mass: 480.2 [M+H]⁺ (rt: 1.42 min).

Example 355N-(2′-fluoro-4′-methoxy-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-N,N′-dimethylsulfuricdiamide

The compound was prepared from the compound of Example 191(c) using themethods of Example 210 (a) and (b). ¹H NMR, 400 MHz: (DMSO-d₆): δ 10.42(s, 1H), 8.95 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.68(s, 2H), 7.6 (t, 1H), 7.52-7.47 (m, 3H), 7.04-7.00 (dd, 1H), 6.97-6.94(s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.8 (s, 6H); LC-MS (ESI):Calculated mass: 520.58; Observed mass: 521 [M+H]⁺ (rt: 1.38 min).

Example 356N-(2′,4′-difluoro-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide

The compound was prepared from the compound Example 334(a) (0.2 g, 0.417mmol) using the method of Example 200(c) and1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.196 g, 0.834 mmol, 2.0 eq.) to give the product in 45% yield (0.095g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H), 8.97 (s, 1H),8.766-8.762 (d, 1H), 8.44-8.42 (dd, 2H), 8.06 (s, 1H), 7.942-7.93 (s,1H), 7.80-7.71 (m, 2H), 7.49-7.42 (m, 2H), 7.31-7.27 (m, 1H), 4.53 (m,1H), 3.18 (s, 1H), 1.48-1.47 (d, 6H); LC-MS (ESI): Calculated mass:508.54; Observed mass: 509.1 [M+H]⁺ (rt: 1.55 min).

Example 357N-(5-(5-(4-aminophenyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedures of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H),8.83 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.79-7.75 (m, 3H), 7.65. 7.63(m, 4H), 7.52 (s, 1H), 7.49-7.39 (m, 2H), 7.29-7.22 (m, 1H), 7.04-7.02(m, 2H), 2.1 (s, 3H); Calculated mass: 454.16; Observed mass: 454.8[M+H]⁺ (rt: 0.58 min).

Example 358N-(5-(6-(4-amino-3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 131(c) using theprocedures of Example 246. ¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H),8.94 (s, 1H), 8.68 (s, 1H), 8.37 (d, 1H), 8.29 (s, 1H), 7.89 (s, 1H),7.71 (m, 2H), 7.55-7.25 (m, 4H), 6.85 (m, 1H), 5.35 (brs, 2H), 2.12 (s,3H); LC-MS (ESI): Calculated mass: 473.15; Observed mass: 474.4 [M+H]⁺(rt: 1.51 min).

Example 3591-Cyclopropyl-3-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)sulfuricdiamide a)1-(5-(5-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-cyclopropylsulfuric diamide

To a solution of5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine(120 mg, 0.2380 mmol) in pyridine was addedN-cyclopropyl-2-oxooxazolidine-3-sulfonamide (78 mg, 0.380 mmol, 1.6eq.). The mixture was stirred at 50° C. for 16 h, quenched with waterand extracted with ethyl acetate (3×50 ml). The combined organic layerwas washed with 1 N HCl and 1N NaOH, water, brine and dried over sodiumsulphate. The solvent was distilled off to afford the crude residuewhich was purified by preparative HPLC to give the product in 10% yield(15 mg).

b)1-Cyclopropyl-3-(2′,4′-difluoro-5-(5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)sulfuricdiamide

The solution of the compound of Example 359(a) (14 mg, 0.0224 mmol) inTFA (1 ml) was heated at 50° C. for 16 h. The mixture was concentratedto give the product in 83% yield (10 mg). ¹H NMR (400 MHz, CD3OD): δ11.8 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.16 (d, 1H), 7.97-7.91 (m,2H), 7.76-7.68 (m, 3H), 7.58-7.55 (m, 1H), 7.50 (t, 1H), 7.46-7.38 (m,3H), 7.28-7.22 (m, 1H), 6.44 (d, 1H), 2.31 (m, 1H), 0.56-0.53 (m, 2H),0.45-0.42 (m, 2H); LC-MS (ESI): Calculated mass: 533.13; Observed mass:534.1 [M+H]⁺ (rt: 1.195 min).

Example 3601-Cyclopropyl-3-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)sulfuricdiamide

The compound was prepared from the compound of Example 2(a) (50 mg,0.1246 mmol) using the procedure of Example 359(a) to give the productin 9.3% yield (6 mg). ¹H NMR (400 MHz, CD₃OD): δ 9.06 (s, 1H), 8.09 (s,1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.77 (s, 2H), 7.69-7.49 (m, 4H),7.18-7.11 (m, 2H), 3.97 (s, 3H), 2.48-2.44 (m, 1H), 0.66-0.53 (m, 4H);LC-MS (ESI): Calculated mass: 520.0; Observed mass: 521.2 [M+H]⁺ (rt:0.94 min).

Example 361N-(2′,4′-difluoro-5-(6-(3-fluoropyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the title compound of Example 131(c)using the procedures of Example 131(d). ¹H NMR (400 MHz, DMSO-d₆): δ10.41 (s, 1H), 9.08 (s, 1H), 8.75 (s, 2H), 8.57 (s, 2H), 8.31 (s, 1H),7.91 (s, 1H), 7.83 (s, 1H), 7.71 (s, 2H), 7.47-7.42 (t, 1H), 7.29-7.25(t, 1H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 459.13; Observedmass: 460.1 [M+H]⁺ (rt: 1.50 min).

Example 362N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

A solution ofN-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(100 mg, 0.181 mmol) in THF/EtOH/Water (5:5:2) was degassed by N₂bubbling for 5 min. 4-Bromo-1-methyl-1H-pyrazol-3-amine (35 mg, 0.19mmol, 1.1 eq.) was added and the mixture was degassed for another 5 min.Bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.009 mmol, 0.05 eq.)and cesium carbonate (170 mg, 0.54 mmol, 3.0 eq.) were addedsequentially and the mixture was further degassed for 5 min and heatedat 90° C. for 16 h. The mixture was quenched and extracted as in Example1(d). The solvent was distilled off to give the crude residue which waspurified by preparative HPLC to give the product in 27% yield (25 mg).¹H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 8.79 (s, 1H), 7.95-7.92 (m, 2H),7.77-7.07 (m, 2H), 7.59 (s, 2H), 7.53-7.47 (m, 3H), 7.29 (m, 1H), 3.75(s, 3H), 2.91 (m, 1H), 1.5-1.49 (d, 2H), 1.30-1.26 (t, 2H), 1.03-1.01(t, 2H); LC-MS (ESI): Calculated mass: 520.5; Observed mass: 521.0[M+H]⁺ (rt: 0.676 min).

Example 363N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 200(b) using theprocedure of Example 200(c) to give the title product in 12% yield (8mg). 1H NMR (300 MHz, CD3OD): δ 8.89 (s, 1H), 7.90 (s, 1H), 7.78-7.74(m, 2H), 7.65-7.54 (m, 4H), 7.51 (d, 1H), 7.15-7.05 (m, 2H), 3.81 (s,3H), 3.31-3.24 (q, 2H), 1.39-1.34 (t, 3H); LC-MS (ESI): Calculated mass:508.54; Observed mass: 509.0 [M+H]⁺ (rt: 0.85 min).

Example 364(Z)—N-(2′,4′-difluoro-5-(5-(1-(hydroxyimino)ethyl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

To a solution ofN-(5-(5-acetyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(110 mg, 0.235 mmol) in ethanol was added hydroxyl amine hydrochloride(24.7 mg, 0.353 mmol) and the mixture was heated at 80° C. for 2 h. Themixture was concentrated under vacuum and washed with ether to affordthe product in 49% yield (55 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s,1H), 8.03 (s, 1H), 7.82-7.70 (m, 3H), 7.60-7.58 (d, 2H), 7.52 (s, 1H),7.46-7.40 (m, 1H), 7.27-7.24 (m, 1H), 2.86-2.83 (m, 1H), 2.25 (s, 3H),1.01-1.00 (m, 4H); LC-MS (ESI): Calculated mass: 482.5; Observed mass:483.1 [M+H]⁺ (rt: 1.475 min).

Example 3652-(5-(1-(5-Acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)acetamidea) Ethyl2-(5-(1-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)acetate

A mixture ofN-(5-(5-ethynyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide(258 mg, 0.6 mmol), ethyl-2-azidoacetate (180 mg, 0.8 mmol, 1.3 eq.),sodium ascorbate (125 mg, 0.6 mmol, 1.0 eq.) and copper sulfatepentahydrate (80 mg, 0.32 mmol, 0.5 eq.) in t-butanol and water (1:1, 3ml) was stirred for 12 h at RT. The mixture was quenched with water andthe precipitate formed was filtered and dried to give the product in 75%yield (250 mg).

b)2-(5-(1-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)aceticacid

To a solution of the compound of Example 365(a) (250 mg, 0.48 mmol) inTHF/methanol/water (1:1:0.5, 5 ml) was added LiOH H₂O (40 mg, 0.968mmol, 2 eq.) and the mixture was stirred at RT for 12 h. The mixture wasconcentrated and the crude product obtained was extracted with ethylacetate and water and dried over sodium sulphate to give the product in42% yield (100 mg).

c)2-(5-(1-(5-acetamido-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1

To a solution of the compound of Example 365(b) (100 mg, 0.2 mmol) inDMF was added HOBt (30 mg, 0.224 mmol, 1.1 eq.) followed by EDC (40 mg,0.224 mmol, 1.1 eq.). The mixture was stirred at RT for 12 h, then 25%ammonia solution was added to the precooled reaction mass and stirredfor 4 h. The mixture was then quenched and extracted as in Example 1(d).The solvent was distilled off to afford the crude residue which waspurified by preparative TLC to give the product in 5% yield (5 mg).

Example 366N-(2′,4′-Difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethenesulfonamide

The compound was prepared from the compound of Example 2(a) (50 mg,0.125 mmol) in THF using the procedure of Example 2(b) and2-chloroethanesulfonyl chloride (30 mg, 0.187 mmol, 1.5 eq.) to affordthe product in 29% yield (18 mg). ¹H NMR (400 MHz, CD₃OD): δ 9.1 (s,1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.76-7.74 (m, 2H),7.63-7.59 (m, 3H), 7.50 (s, 1H), 7.14-7.12 (m, 2H), 6.80-6.78 (m, 1H),6.31-6.27 (d, 1H), 6.09-6.06 (d, 1H), 3.95 (s, 3H); LC-MS (ESI):Calculated mass: 491.5; Observed mass: 492.1 [M+H]⁺ (rt: 1.413 min).

Example 367N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-hydroxyethanesulfonamidea)2-(Benzyloxy)-N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo-[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 2(a) (100 mg,0.249 mmol) in THF using the method of Example 2(b) and2-(benzyloxy)ethanesulfonyl chloride (87 mg, 0.374 mmol, 1.5 eq.) togive the product in 69% yield (100 mg). LC-MS (ESI): Calculated mass:512.55; Observed mass: 513.1 [M+H]⁺ (rt: 0.632 min).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-hydroxyethanesulfonamide

To a solution of the compound of Example 367(a) (100 mg, 0.17 mmol) inmethanol (2 ml) and THF (1 ml) was added 10% Pd/C (10 mg, 0.1 eq.) andpalladium hydroxide on carbon (10 mg, 0.1 eq). The reaction vessel waspurged with N₂ for 5 min. The mixture was then hydrogenated with H₂ for12 h. The mixture was filtered through a pad of celite and the filtratewas concentrated to give the compound in 13% yield (11 mg). ¹H NMR (400MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.9 (s, 1H), 8.23 (s, 1H), 8.00-7.97 (d,2H), 7.76-7.58 (m, 5H), 7.48 (s, 2H), 7.29 (d, 1H), 3.88 (s, 3H), 3.81(t, 4H). LC-MS (ESI): Calculated mass: 509.53; Observed mass: 510.1[M+H]⁺ (rt: 0.853 min).

Example 368N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)piperidine-4-carboxamide

The title compound was prepared from the compound of Example 2(a) usingthe procedures of Example 240. ¹H NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H),8.11 (s, 1H), 8.0 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H),7.71 (s, 1H), 7.69 (s, 1H), 7.65-7.59 (m, 2H), 7.52 (m, 1H), 7.14-7.1(m, 2H), 3.94 (s, 1H), 2.89 (t, 4H), 2.7 (m, 1H), 2.04-1.84 (m, 4H):LC-MS (ESI): Calculated mass: 512.55; Observed mass: 513.2 [M+H]⁺ (rt:1.0 min).

Example 369N-(5-(5-(4,5-dihydrooxazol-2-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamidea)N-(5-((4-(4,5-dihydrooxazol-2-yl)-2-nitrophenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 22(a) (0.25 g, 0.608 mmol) intert-butanol was added 2-amino ethanol (0.05 ml, 0.912 mmol, 1.5 eq.)and stirred at RT for 30 min. Iodine (0.25 g, 1.82 mmol, 3 eq.) andK₂CO₃ (0.25 g, 1.82 mmol, 3 eq.) were added and the mixture was stirredat 75° C. for 24 h. The mixture was quenched with sodium thiocyanatesolution and extracted with ethyl acetate (3×50 ml). The solvent wasdistilled off to give the crude residue which was purified by combiflashchromatography (5% methanol in chloroform) to give the product in 60%yield (0.15 g).

b)N-(5-((2-amino-4-(4,5-dihydrooxazol-2-yl)phenyl)amino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 369(a) (150 mg, 0.33 mmol) inTHF (3 ml) were added a solution of ammonium chloride (70 mg, 1.32 mmol,4 eq.) in water (1 ml) and zinc (86 mg, 1.32 mmol, 4 eq.). The mixturewas stirred at RT for 2 h and filtered. The filtrate was diluted withwater and extracted as in Example 1(d). The solvent was distilled off toafford the product in 78% yield (0.11 g).

c)N-(5-(5-(4,5-dihydrooxazol-2-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the the compound of Example 369(b) usingthe procedure of Example 22(d) to give the product in 78% yield (0.11g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.5 (s, 1H), 8.84 (s, 1H), 8.7 (d,1H), 8.13 (t, 1H), 8.10-8.05 (m, 3H), 7.85-7.72 (m, 3H), 7.54 (s, 1H),7.49-7.43 (m, 1H), 4.47 (t, 2H), 3.31 (t, 2H), 2.12 (s, 3H). LC-MS(ESI): Calculated mass: 432.4; Observed mass: 432.8 [M+H]⁺ (rt: 0.288min).

Example 370N-(5-(5-(1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 313(d) using theprocedures of Example 313(e). ¹H NMR (400 MHz, DMSO-d₆): δ 10.49 (s,1H), 9.73 (s, 1H), 8.83 (s, 1H), 8.43 (s, 1H), 8.06 (t, 2H), 7.88 (t,2H), 7.79-7.73 (m, 1H), 7.55 (s, 1H), 7.49-7.43 (m, 1H), 7.29-7.25 (m,1H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 431.4; Observed mass:432.8 [M+H]⁺ (rt: 1.485 min).

Example 371N-(5-(5-(4,5-dihydrooxazol-2-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 369 using theprocedures of Example 2. ¹H NMR (300 MHz, CD₃OD): δ 8.59 (s, 1H), 8.27(d, 1H), 8.15-8.14 (t, 1H), 8.11 (m, 1H), 7.82-7.75 (m, 4H), 7.66-7.56(m, 1H), 7.56 (m, 1H), 7.13-7.11 (m, 1H), 6.56 (t, 1H), 3.53-3.47 (m,2H), 3.0 (m, 2H), 2.82 (s, 3H), 2.7 (m, 1H), 2.14-2.0 (m, 4H). LC-MS(ESI): Calculated mass: 512.55; Observed mass: 513.1 [M+H]⁺ (rt: 0.632min).

Example 3721-(2′,4′-Difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-3-(furan-2-ylmethyl)sulfuricdiamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 245 to give the pure product in 10% yield (7 mg).¹H NMR (300 MHz, DMSO-d₆): δ 10.26 (s, 1H), 8.66 (s, 1H), 8.2 (s, 0.1H),7.98 (s, 1H), 7.94 (s, 1H), 7.75-7.67 (m, 2H), 7.57 (t, 3H), 7.45-7.43(m, 2H), 7.29-7.25 (m, 2H), 7.22 (m, 2H), 3.87 (s, 3H), 3.17 (s, 2H);LC-MS (ESI): Calculated mass: 479.5; Observed mass: 480.2 [M+H]⁺ (rt:1.34 min).

Example 373N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-1-methylpiperidine-4-carboxamide

The compound was prepared from the compound of Example 2(a) using theprocedures of Example 233. ¹H NMR (400 MHz, CD₃OD): δ 9.11 (s, 1H), 8.23(t, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 7.80-7.77 (m, 3H),7.65-7.61 (m, 2H), 7.14-7.12 (m, 2H), 3.96 (s, 3H), 3.63-3.60 (m, 2H),3.088-3.082 (m, 2H), 2.90 (s, 3H), 2.79-2.73 (m, 1H), 2.24-2.01 (m, 4H);LC-MS (ESI): Calculated mass: 526.58; Observed mass: 527.2 [M+H]⁺ (rt:0.183 min).

Example 3742′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-ola) 1-bromo-3-methoxy-5-nitrobenzene

To a solution of 1-bromo-3,5-dinitrobenzene (5 g, 20.2 mmol) in methanol(50 ml) was added sodium methoxide (1.3 g, 24.3 mmol, 1.2 eq.) and themixture was heated to reflux for 12 h and then quenched with 10% HCl.The solid formed was filtered and dried to afford the compound in 65%yield (3 g).

b) 3-bromo-5-methoxyaniline

To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) inTHF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). Themixture was stirred at RT for 30 min and filtered. The filtrate wasdiluted with water and extracted as in Example 1(d). The solvent wasdistilled off to afford the product in 92% yield (0.8 g).

c)N-(3-bromo-5-methoxyphenyl)-4-(1-methyl-1H-pyrazol-4-yl)-2-nitroaniline

A solution of the compound of Example 374(b) (1 g, 4.78 mmol, 1.2 eq.),3-bromo-5-methoxyaniline (0.8 g, 3.98 mmol) and potassium fluoride (0.23g, 3.98 mmol, 1 eq.) in DMF was heated at 120° C. for 12 h. The mixturewas quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the crude residue which was purified by columnchromatography (60-120 silica gel, 50% ethyl acetate in hexane) to givethe product in 42% yield (0.81 g).

d)1-(3-Bromo-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazole

The compound was prepared using the procedures of Example 1(g) and 1(h)starting from the compound of Example 374(c) (0.81 g, 2.02 mmol) toafford the product in 52% yield (0.35 g).

e)1-(2′,4′-Difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

The compound was prepared from the compound of Example 374(d) (0.35 g,0.92 mmol) using the procedure of Example 277(d) and 2,4-difluorophenylboronic acid (0.17 g, 1.09 mmol, 1.2 eq.) to yield the product in 25%yield (95 mg).

f)2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-ol

To a slurry of aluminium chloride (77 mg, 0.576 mmol) and thiourea (15mg, 0.192 mmol) in DCM (5 ml) was added a solution of the compound ofExample 374(e) (80 mg, 0.192 mmol) in DCM (3 ml). The mixture was heatedat 50° C. for 5 h. The mixture was quenched and extracted as in Example2(d) and dried over anhydrous Na₂SO₄ and concentrated to afford theproduct in 17% yield (15 mg). ¹H NMR (400 MHz, CD₃OD): δ 9.2 (s, 1H),8.07 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.77 (s, 2H), 7.64-7.58 (m,1H), 7.30 (s, 1H), 7.17-7.07 (m, 4H), 3.95 (s, 3H). LC-MS (ESI):Calculated mass: 402.4; Observed mass: 403.1 [M+H]⁺ (rt: 1.282 min).

Example 375N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)pyrazin-2-amine

A solution of the compound of Example 2(a) (100 mg, 0.24 mmol) intoluene (6 ml) was degassed by N₂ bubbling for 5 min. 2-Chloro pyrazine(34 g, 0.29 mmol, 1.2 eq.) was added and the mixture was degassed foranother 5 min. Pd₂(dba)₃ (22 mg, 0.02 mmol, 0.1 eq.) and xantphos (28mg, 0.04 mmol, 0.2 eq.) and Cs₂CO₃ (242 mg, 0.74 mmol, 3.0 eq) wereadded sequentially and the mixture was further degassed for 5 min andthen heated at 110° C. for 16 h. The mixture was filtered on celite bedand quenched and extracted as in Example 1(d). The solvent was distilledoff to afford the crude residue which was purified by preparative HPLCto yield the product in 10% yield (11 mg). ¹H NMR (400 MHz, DMSO-d₆): δ9.99 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.26-8.25 (m, 1H), 8.19 (m,2H), 8.00-7.98 (m, 3H), 7.93 (s, 1H), 7.85 (d, 1H), 7.79-7.34 (m, 2H),7.62-7.59 (dd, 1H), 7.47-7.4 (m, 2H), 7.28-7.24 (dt, 1H), 3.87 (s, 3H).LC-MS (ESI): Calculated mass: 479.48; Observed mass: 480.1 [M+H]⁺ (rt:1.54 min).

Example 376N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)isoxazol-3-aminea)1-(5-Bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

To a solution of the compound of Example 2(a) (0.80 g, 1.995 mmol) inHBr (8 ml) was added aqueous solution of NaNO₂ (0.26 g in 2 ml of water)and the mixture was stirred at 0° C. for 20 min. Then CuBr in HBr (0.572g, 3.99 mmol, 2.0 eq in 3 ml of HBr) was added at 0° C. and the mixturewas stirred at 50° C. for 10 min. The mixture was quenched and extractedas in Example 1(d). The solvent was distilled off under reduced pressureto afford the product in 80.9% yield (0.750 g). LC-MS (ESI): Calculatedmass: 465.2; Observed mass: 467.0 [M+H]⁺ (rt: 1.75 min).

b)N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)isoxazol-3-amine

The compound was prepared from the compound of Example 376(a) followingthe method of Example 280. ¹H NMR (400 MHz, CD₃OD): δ 8.53 (s, 1H),8.43-8.42 (d, 1H), 8.03 (s, 1H), 7.95-7.93 (m, 2H), 7.89 (s, 1H),7.76-7.45 (d, 1H), 7.68-7.62 (m, 3H), 7.33-7.32 (d, 1H), 7.16-7.11 (m,2H), 6.23-6.22 (d, 1H), 6.23-6.27 (m, 1H), 3.97 (s, 3H). LC-MS (ESI):Calculated mass: 468.46; Observed mass: 468.46 [M+H]⁺ (rt: 1.282 min).

Example 377N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)pyridazin-3-amine

The compound was prepared from the compound of Example 376(a) followingthe procedure described in the Example 280. ¹H NMR (400 MHz, DMSO-d₆): δ9.75 (s, 1H), 8.74-8.73 (d, 2H), 8.65 (s, 1H), 8.34-8.33 (m, 1H), 8.19(s, 1H), 7.98 (s, 1H), 7.94 (m, 2H), 7.78-7.75 (m, 2H), 7.6-7.57 (dd,1H), 7.53-7.4 (m, 3H), 7.4-7.2 (m, 2H), 3.87 (s, 3H). LC-MS (ESI):Calculated mass: 479.48; Observed mass: 403.1 [M+H]⁺ (rt: 1.282 min).

Example 378N-(4′-cyano-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamidea)3-bromo-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)aniline

To a solution of the compound of Example 277(c) (1.6 g, 3.89 mmol) inethanol (15 ml) was added aqueous solution of NaOH (1.56 g, 38.9 mmol,10.0 eq.) and the mixture was heated at 85° C. for 5 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offunder reduced pressure to afford the product in 90% yield (1.3 g).

b)N-(3-bromo-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-phenyl)cyclopropanesulfonamide

To a solution of the compound of Example 378(a) (200 mg, 0.54 mmol) inDCM was added pyridine (86 mg, 1.08 mmol, 2.0 eq.) followed bycyclopropane sulfonyl chloride (93 mg, 0.65 mmol, 1.2 eq.). The mixturewas stirred for 1 h, and quenched and extracted as in Example 2(b). Thesolvent was distilled off under reduced pressure to afford the productin 59% yield (75 mg).

c)N-(4′-cyano-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-15 [1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 378(b) (100 mg,0.21 mmol) using the procedure of Example 200(c) and 4-cyano phenylboronic acid (38 mg, 0.32 mmol, 2.5 eq.) to give the product in 24%yield (25 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.2-10.3 (brS, 1H), 8.71(s, 1H), 8.19 (s, 1H), 8.02-7.94 (m, 6H), 7.77 (s, 1H), 7.69-7.67 (d,1H), 7.6-7.58 (m, 3H), 3.87 (s, 3H), 2.91-2.88 (m, 1H), 1.0 (d, 4H).LC-MS (ESI): Calculated mass: 494.59; Observed mass: 495.15 [M+H]⁺ (rt:1.4 min).

Example 379N-(2′,4′-difluoro-5-(5-(4-methylpiperazine-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 332(b) (100 mg, 0.23 mmol, 1.0eq.) in 1,4-dioxane (5 ml) was added trimethyl aluminium (49 mg, 0.59mmol, 2.5 eq). The mixture was stirred for 10 min and then N-methylpiperazine (35 mg, 0.35 mmol, 1.5 eq.) was added and the mixture washeated at 110° C. in a sealed tube for 12 h. The mixture was cooled toRT and filtered through celite and the filtrate was concentrated toafford the crude product which was purified by preparative HPLC toafford the product in 21% yield (24 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.61(s, 1H), 8.1 (s, 1H), 7.86 (s, 1H), 7.79. 7.77 (d, 1H), 7.75 (d, 1H),7.68-7.6 (m, 1H), 7.51 (d, 1H), 7.48-7.46 (d, 1H), 7.14-7.08 (m, 2H),3.8-3.5 (br, 4H), 2.6-2.4 (br, 4H), 2.35 (s, 3H), 2.18 (s, 3H). LC-MS(ESI): Calculated mass: 489.52; Observed mass: 489.8 [M+H]⁺ (rt: 0.15min).

Example 381N-(5-(5-cyano-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamidea)1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of the compound of Example 313(c) (1.0 g, 2.88 mmol, 1.0eq.) in ethanol (20 ml) was added KOH (0.486 g, 8.66 mmol, 3.0 eq.) as a20% aqueous solution and the mixture was heated at 80° C. for 6 h. Thesolvent was distilled off under reduced pressure and the crude materialwas stirred with water and ethyl acetate. The ethyl acetate was driedover sodium sulphate and concentrated to afford the product in 78% yield(0.7 g).

b)N-(5-(5-cyano-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)ethanesulfonamide

The compound was prepared from the compound of Example 380(a) (100 mg,0.28 mmol) and ethanesulfonyl chloride (40 mg, 0.31 mmol, 1.1 eq.) usingthe procedure of Example 2(b) to give the product in 16% yield (22 mg).¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.4 (s, 1H), 7.86-7.73 (m,3H), 7.58-7.45 (m, 4H), 7.29-7.25 (t, 1H), 3.3 (m, 2H), 1.27-1.24 (t,3H). LC-MS (ESI): Calculated mass: 438.45; Observed mass: 438.9 [M+H]⁺(rt: 1.5 min).

Example 3811-(2′,4′-difluoro-5-methyl-[1,1′-biphenyl]-3-yl)-5-(l-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazolea) 2,4-Difluoro-5′-methyl-3′-nitrobiphenyl

The compound was prepared from 1-bromo-3-methyl-5-nitro-benzene (1.5 g,6.94 mmol) and difluorophenyl boronic acid (1.3 g, 8.33 mmol, 1.2 eq.)using the procedure of Example 1(d) to afford the product in 27% yield(0.65 g).

b) 2′,4′-difluoro-5-methyl-[1,1′-biphenyl]-3-amine

To a solution of the compound of Example 381(a) (1.4 g, 5.62 mmol) inTHF (20 ml) were added a solution of ammonium chloride (2.4 g, 44.9mmol, 8 eq.) in water (8 ml) and zinc (2.92 g, 44.9 mmol, 8 eq.). Themixture was stirred at RT for 2 h and filtered. The filtrate was dilutedwith water and extracted as in Example 1(d). The solvent was distilledoff to afford the product in 92% yield (1.3 g).

c)1-(2′,4′-difluoro-5-methyl-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

The compound was prepared from the compound of Example 381(b) (1.3 g,5.93 mmol) using the procedures of Example 1 steps (f) to (i) to givethe product in 10% yield (20 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s,1H), 8.24 (s, 1H), 8.00-7.97 (d, 2H), 7.77-7.72 (m, 2H), 7.67-7.62 (m,3H), 7.53 (s, 1H), 7.5-7.4 (t, 1H), 7.3-7.2 (t, 1H), 3.9 (s, 6H). LC-MS(ESI): Calculated mass: 400.42; Observed mass: 401.1 [M+H]⁺ (rt: 1.6min).

Example 382N-(5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-3′-(1H-pyrazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 277(c) using theprocedure described in Example 277(d). ¹H NMR (400 MHz, DMSO-d₆): δ 9.1(s, 1H), 8.65 (d, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.03(s, 1H), 7.98 (s, 2H), 7.94-7.92 (d, 1H), 7.81-7.8 (d, 1H), 7.77-7.5 (d,1H), 7.7-7.64 (m, 4H), 6.59 (s, 1H), 2.1 (s, 1H). LC-MS (ESI):Calculated mass: 473.53; Observed mass: 474.2 [M+H]⁺ (rt: 0.47 min).

Example 383N-(5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-4′-(1H-pyrrol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 277(c) using theprocedure described in Example 277(d). ¹H NMR (400 MHz, DMSO-d₆): δ 8.71(s, 1H), 8.2 (s, 1H), 8.03 (s, 1H), 7.99 (s, 1H), 7.94-7.93 (m, 2H),7.86-7.83 (m, 2H), 7.76-7.68 (m, 4H), 7.6-7.48 (m, 3H), 6.3 (d, 1H),3.88 (s, 3H), 2.14 (s, 3H): LC-MS (ESI): Calculated mass: 472.54;Observed mass: 473.1 [M+H]⁺ (rt: 1.39 min).

Example 384N-(2′,4′-difluoro-5-(5-morpholino-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamideusing the procedure of Example 321. ¹H NMR (400 MHz, DMSO-d₆): δ 10.38(s, 1H), 9.0 (s, 1H), 7.79-7.73 (m, 1H), 7.67 (s, 1H), 7.64 (s, 1H),7.61 (s, 1H), 7.53-7.46 (m, 2H), 7.33-7.26 (m, 3H), 3.9 (s, 4H), 3.2 (s,4H), 2.9 (m 1H), 1.05 (d, 4H): LC-MS (ESI): Calculated mass: 510.56;Observed mass: 473.1 [M+H]⁺ (rt: 1.39 min).

Example 385(E)-N-(2′,4′-difluoro-5-(5-(1-(methoxyimino)ethyl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(5-(5-acetyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamideusing the method described in Example 364. ¹H NMR (400 MHz, DMSO-d₆): δ8.69 (s, 1H), 9.0 (s, 1H), 8.03 (d, 1H), 7.76-7.67 (m, 3H), 7.54 (m,2H), 7.47 (m, 1H), 7.45-7.42 (m, 2H), 7.28-7.22 (m, 3H), 7.25-7.24 (dt,1H), 3.92 (s, 3H), 2.84-2.81 (m, 1H), 2.26 (s, 3H), 1.0 (d, 4H): LC-MS(ESI): Calculated mass: 496.53; Observed mass: 497.0 [M+H]⁺ (rt: 1.68min).

Example 386N-(5-(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamideusing the procedure described in Example 200(c). ¹H NMR (400 MHz,DMSO-d₆): δ 8.4 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H),7.8-7.7 (m, 1H), 7.69 (s, 1H), 7.61 (m, 2H), 7.5-7.4 (m, 2H), 7.32-7.25(dt, 1H), 4.8-4.65 (m, 1H), 2.95-2.15-1.6 (m, 8H), 1.02 (d, 4H): LC-MS(ESI): Calculated mass: 559.63; Observed mass: 560.3 [M+H]⁺ (rt: 1.19min).

Example 387N-(2′,4′-difluoro-5-(5-(2-oxopyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

A solution ofN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(50 mg, 0.099 mmol, 1 eq.) in DMSO (2 ml) was degassed by nitrogenbubbling for 10 min. Copper(I)iodide (11.3 mg, 0.059 mmol, 0.6 eq.),K₂CO₃ (42 mg, 0.298 mmol, 3 eq.), N,N-dimethyl glycine HCl (11 mg, 0.079mmol) and 2-pyrrolidone (42 mg, 0.49 mmol, 5 eq.) were added and themixture was further degassed for 10 min and then heated to 110° C. for16 h. The mixture was cooled to RT and diluted with ethyl acetate,filtered through a celite bed and washed with water and brine solution.The ethyl acetate layer was dried over sodium sulphate. The solvent wasdistilled off to afford the crude residue which was purified bypreparative HPLC to afford the product in 90% yield (45 mg). ¹H NMR (400MHz, DMSO-d₆): δ 8.65 (s, 1H), 7.96 (d, 1H), 7.78-7.65 (m, 3H), 7.54 (m,2H), 7.45-7.42 (m, 2H), 7.28-7.24 (dt, 1H), 3.9 (t, 2H), 2.88-2.8 (m,1H), 2.12-2.02 (m, 2H), 1.0 (m, 4H): LC-MS (ESI): Calculated mass:508.54; Observed mass: 508.7 [M+H]⁺ (rt: 1.46 min).

Example 388N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(1H-pyrazol-4-yl)phenyl)acetamide

The compound was prepared from the compound of Example 277(c) using theprocedure described in Example 277(d). ¹H NMR (400 MHz, DMSO-d₆): δ 10.3(s, 1H), 8.61 (s, 1H), 8.2 (s, 1H), 8.11 (br, 1H), 7.98 (s, 1H), 7.94(s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.66-7.57 (m, 3H), 3.88 (s, 3H),1.84 (s, 3H): LC-MS (ESI): Calculated mass: 397.43; Observed mass:398.22 [M+H]⁺ (rt: 1.46 min).

Example 389N-(3-(3-fluoropyridin-4-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamide

The compound was prepared from the compound of Example 277(c) using theprocedure described in Example 277(d). ¹H NMR (400 MHz, DMSO-d₆): δ 10.5(s, 1H), 8.97 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.58 (s, 1H), 8.24(s, 1H), 8.2 (s, 1H), 8.02 (s, 1H), 7.97-7.96 (m, 2H), 7.8-7.65 (m, 4H),3.89 (s, 3H), 2.13 (s, 3H); LC-MS (ESI): Calculated mass: 426.45;Observed mass: 427.1 [M+H]⁺ (rt: 0.26 min).

Example 390N-(5-(5-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

To a solution of the compound of Example 326 (50 mg, 0.116 mmol) in DCMwas added pyridine (0.5 ml) followed by cyclopropanesulfonyl chloride(20 mg, 0.139 mmol, 1.2 eq.). The mixture was stirred for 1 h, andquenched and extracted as in Example 2(b). The solvent was distilled offto afford the crude residue which was purified by preparative HPLC togive the product in 90% yield (42 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.58(s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H),7.74-7.62 (m, 4H), 7.49 (s, 1H), 7.17-7.08 (m, 2H), 3.0 (m, 1H), 2.2 (s,3H), 1.1 (d, 4H); LC-MS (ESI): Calculated mass: 533.5; Observed mass:534.1 [M+H]⁺ (rt: 1.61 min).

Example 391N-(2′-fluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared fromN-(2′-fluoro-5-nitro-[1,1′-biphenyl]-3-yl)-acetamide using theprocedures of Example 1, 2 and 200(c) to afford the product in 26.6%yield (20 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1H), 8.03 (s, 1H),7.94 (s, 1H), 7.89 (s, 1H), 7.71-7.69 (m, 1H), 7.65-7.6 (m, 5H),7.53-7.49 (m, 2H), 7.35-7.25 (m, 2H), 3.96 (s, 3H), 2.78-2.73 (m, 1H),1.17-1.0 (m, 4H); LC-MS (ESI): Calculated mass: 487.55; Observed mass:488.6 [M+H]⁺ (rt: 1.45 min).

Example 392N-(2′,4′-difluoro-5-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamidea) tert-butyl4-(4-(1-(5-(cyclopropanesulfonamido)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The compound was prepared fromN-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide(100 mg, 0.19 mmol) using the procedure of Example 200(c) to afford thetitle product in 26.6% yield (20 mg).

b)N-(2′,4′-difluoro-5-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared from the compound of Example 392(a) (60 mg,0.08 mmol) using the procedure of 331(b) to afford the product in 40%yield (0.020 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.30 (s,1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.76-7.74 (m, 1H), 7.69-7.62 (m, 2H),7.54-7.53 (t, 1H), 7.49 (s, 1H), 7.46-7.43 (m, 1H), 7.27 (t, 3H), 4.23(m, 1H), 3.12-3.09 (d, 2H), 2.81 (m, 1H), 2.70-2.64 (t, 2H), 2.04-2.01(d, 2H), 1.88-1.84 (m, 2H), 1.23 (s, 2H), 1.00-0.99 (m, 2H), 0.97 (s,1H); LC-MS (ESI): Calculated mass: 574.20; Observed mass: 574.8 [M+H]⁺(rt: 0.27 min).

Example 393N-(2′,4′-difluoro-5-(5-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide

The compound was prepared using the procedures of Example 392. ¹H NMR(400 MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.98 (s,1H), 7.78-7.72 (q, 1H), 7.69-7.62 (q, 2H), 7.55-7.52 (d, 2H), 7.48-7.42(m, 2H), 7.30-7.25 (m, 1H), 4.87-4.82 (m, 1H), 3.34-3.16 (m, 2H),3.14-2.94 (m, 3H), 2.93-2.80 (m, 2H), 2.26-2.21 (m, 1H), 2.14-2.07 (m,1H), 1.01-0.98 (d, 4H); LC-MS (ESI): Calculated mass: 560.62; Observedmass: 561.3 [M+H]⁺ (rt: 0.39 min).

Example 394N-(5-(5-(4-amino-3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide

The compound was prepared from the compound of Example 1(h) using theprocedure of Example 253. ¹H NMR (300 MHz, DMSO-d₆): δ 10.46 (s, 1H),8.86 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.81-7.71 (m, 3H), 7.59 (d,1H), 7.51-7.40 (m, 3H), 7.33-7.24 (m, 2H), 6.88-6.82 (m, 1H), 5.25 (brs,2H), 2.12 (s, 3H); LC-MS (ESI): Calculated mass: 472.15; Observed mass:473.5 [M+H]⁺ (rt: 1.47 min).

Example 395N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)-2-(4-methylpiperazin-1-yl)acetamide

The compound was prepared from the compound of Example 2(a) using theprocedure of Example 233. ¹H NMR (300 MHz, DMSO-d₆): δ 10.37 (s, 1H),8.89 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H),7.89 (s, 1H), 7.76-7.72 (m, 2H), 7.66-7.64 (m, 2H), 7.6 (s, 1H),7.49-7.44 (m, 1H), 7.31-7.26 (dt, 1H), 3.88 (s, 3H), 3.46 (s, 3H),3.5-3.4 (br, 2H), 3.16 (s, 4H), 2.8 (s, 4H); LC-MS (ESI): Calculatedmass: 541.59; Observed mass: 542.1 [M+H]⁺ (rt: 0.1 min).

Example 396N-(3-(5-fluoropyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)cyclopropanesulfonamidea)N-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A solution of the compound of Example 277(c) (0.9 g, 2.2 mmol) in1,4-dioxane (20 ml) was degassed by N₂ bubbling for 5 min.Bis(pinacolato)diboron (0.67 g, 0.1855 mmol, 1.2 eq.) was added and themixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.0107 g, 0.0131mmol, 0.05 eq.) and potassium acetate (0.539 g, 5.49 mmol, 2.5 eq.) wereadded sequentially and the mixture was further degassed for 5 min andthen heated at 100° C. for 12 h. The mixture was quenched and extractedas in Example 1(d). The solvent was distilled off to afford the cruderesidue, which was washed with hexane to afford the title crude product(1.1 g). ¹H NMR (300 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.58 (s, 1H),8.19-8.18 (m, 1H), 7.98-7.94 (m, 3H), 7.58 (m, 2H), 7.49 (m, 1H), 3.89(s, 3H), 2.10 (s, 3H), 1.33 (s, 6H), 1.17 (s, 6H); LC-MS (ESI):Calculated mass: 457.23; Observed mass: 457.90 [M+H]⁺ (rt: 0.480-0.493min).

b)N-(3-(5-fluoropyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)phenyl)acetamide

A solution of 2-bromo-5-fluoropyridine (0.2 g, 1.136 mmol) in1,2-dimethoxyethane (16 ml) was degassed by N₂ bubbling for 5 min. Thecompound of Example 396(a) (1.03 g, 2.253 mmol, 2.0 eq.) was added andthe mixture was degassed for another 5 min. Pd(dppf)Cl₂ (0.0463 g,0.0567 mmol, 0.05 eq.) and aqueous sodium carbonate (0.3 g, 2.83 mmol,2.5 eq.) were added sequentially and the mixture was further degassedfor 5 min and then heated at 90° C. for 3 h. The mixture was quenchedand extracted as in Example 1(d). The solvent was distilled off toafford the crude residue which was purified by column chromatography(60-120 silica gel, 3% methanol in DCM) to afford the title product in52% yield (250 mg). ¹H NMR (400 MHz, DMSO-d6): δ 8.59 (m, 1H), 8.53 (s,1H), 8.19 (m, 1H), 8.13 (m, 1H), 8.03-8.01 (m, 1H), 7.96-7.91 (m, 1H),7.88 (m, 1H), 7.76-7.71 (m, 1H), 7.65-7.57 (m, 3H), 7.56-7.48 (m, 1H),3.89 (s, 3H), 2.10 (s, 3H). LC-MS (ESI): Calculated mass 426.16;Observed mass: 427.1 [M+H]⁺ (rt: 0.491 min).

c)3-(5-Fluoropyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]-imidazol-1-yl)aniline

To a solution of the compound of Example 396(b) (250 mg, 0.586 mmol) inethanol (30 ml) was added aqueous solution of NaOH (230 mg, 5.75 mmol,10 eq.) and the mixture was heated at 85° C. for 16 h. The mixture wasquenched and extracted as in Example 1(d). The solvent was distilled offto afford the crude residue which was taken to the next step withoutfurther purification. Yield 250 mg. LC-MS (API): Calculated mass:384.15; Observed mass: 385.2 [M+H]⁺ (rt: 0.312 to 0.413 min).

d)N-(3-(5-fluoropyridin-2-yl)-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)cyclopropanesulfonamide

To a solution of the compound of Example 396(c) (250 mg, 0.651 mmol) inTHF (15 ml) was added pyridine (0.154 g, 1.946 mmol, 3.0 eq.) followedby cyclopropanesulfonyl chloride (0.11 g, 0.7746 mmol, 1.2 eq.). Thereaction was stirred at RT for 12 h, and quenched and extracted as inExample 1(d). The solvent was distilled off to afford the crude residuewhich was purified by preparative HPLC to afford the product in 5% yield(15.6 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 8.74-8.73 (d,1H), 8.70 (s, 1H), 8.22-8.18 (m, 2H), 8.07-8.00 (m, 3H), 7.94-7.91 (m,2H), 7.67-7.65 (m, 1H), 7.61-7.59 (m, 2H), 3.87 (s, 3H), 2.84 (m, 1H),1.01-0.996 (m, 4H); LC-MS (ESI): Calculated mass: 488.14; Observed mass:489.1 [M+H]⁺ (rt: 0.847 to 1.048 min).

Abbreviations

-   RT—Room temperature-   rt—Retention time-   BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   DMF—N,N-dimethylformamide-   THF—Tetrahydrofuran-   TEA—Triethyl amine-   DCM—Dichloromethane-   DMSO—Dimethylsulfoxide-   EDC—1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride-   HATU—2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate methanaminium-   HOBt—Hydroxybenzotriazole-   DIPEA—N,N-diisopropylethylamine-   TBAF—tetra-n-butylammonium fluoride-   Pd(dppf)Cl₂-1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride-   Pd(PPh₃)₄—Tetrakis(triphenylphosphine)palladium(0)-   Pd₂(dba)₃—Tris(dibenzylideneacetone)dipalladium(0)

1-18. (canceled)
 19. A compound of formula (Ia)

wherein Z is CH; A is a pyrazolyl ring; R₁ is H; R₂ is C₁₋₇ alkyl; B isphenyl; R₃ and R₄ are halogen; M is —NHSO₂R₈; R₈ is C₁₋₇ alkyl or C₃₋₇cycloalkyl; or a pharmaceutically acceptable salt thereof.
 20. Thecompound according to claim 1, wherein R₃ is fluoro.
 21. The compoundaccording to claim 1, wherein R₄ is fluoro.
 22. The compound accordingto claim 1, wherein R₂ is methyl.
 23. The compound according to claim 1,wherein R₈ is cyclopropyl.
 24. The compound according claim 1, which isN-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)methanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)ethanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)propane-2-sulfonamide;N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)cyclopropanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-biphenyl-3-yl)cyclopentanesulfonamide;N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide;N-(2′,6′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide;N-(2′,4′-difluoro-5-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide;N-(2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)ethanesulfonamide;or or a pharmaceutically acceptable salt thereof.